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1. Design, Synthesis, and In Vitro Antimalarial Evaluation of New 1,3,5-Tris[(4-(Substituted-Aminomethyl)Phenoxy)Methyl]Benzenes

Author: Sandra Albenque-Rubio, Jean Guillon, Patrice Agnamey, Céline Damiani, Solène Savrimoutou, Romain Mustière, Noël Pinaud, Stéphane Moreau, Jean-Louis Mergny, Luisa Ronga, Ioannis Kanavos, Mathieu Marchivie, Serge Moukha, Pascale Dozolme, Pascal Sonnet, and Anita Cohen
Subjects: antimalarial activity, 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene, G-quadruplexes, synthesis, Pharmacy and materia medica, RS1-441, Chemistry, QD1-999
Abstract: By taking into account our previously described series of 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds, we have now designed, prepared, and evaluated in vitro against Plasmodium falciparum a novel series of structural analogues of these molecules, i.e., the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives. The pharmacological data showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new nitrogen polyphenoxymethylbenzene compounds was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivative 1m was found as one of the most potent and promising antimalarial candidates with favorable cytotoxic to antiprotozoal properties in the P. falciparum strains W2 and 3D7. In conclusion, this 1,3,5-tris[(4-(pyridin-3-ylmethylaminomethyl)phenoxyl)methyl]benzene 1m (IC50 = 0.07 μM on W2, 0.06 μM on 3D7, and 62.11 μM on HepG2) was identified as the most promising antimalarial derivative with selectivity indexes (SI) of 887.29 on the W2 P. falciparum chloroquine-resistant strain, and of 1035.17 on the chloroquine-sensitive and mefloquine decreased sensitivity strain 3D7. It has been previously described that the telomeres of P. falciparum could represent potential targets for these types of polyaromatic compounds; therefore, the capacity of our novel derivatives to stabilize the parasitic telomeric G-quadruplexes was assessed using a FRET melting assay. However, with regard to the stabilization of the protozoal G-quadruplex, we observed that the best substituted derivatives 1, which exhibited some interesting stabilization profiles, were not the most active antimalarial compounds against the two Plasmodium strains. Thus, there were no correlations between their antimalarial activities and selectivities of their respective binding to G-quadruplexes.
Published: 2024
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2. Synthesis and Antimalarial Evaluation of New 1,3,5-tris[(4-(Substituted-aminomethyl)phenyl)methyl]benzene Derivatives: A Novel Alternative Antiparasitic Scaffold

Author: Sandra Albenque-Rubio, Jean Guillon, Anita Cohen, Patrice Agnamey, Solène Savrimoutou, Stéphane Moreau, Jean-Louis Mergny, Luisa Ronga, Ioannis Kanavos, Serge Moukha, Pascale Dozolme, and Pascal Sonnet
Subjects: antimalarial activity, 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene, antileishmanial activity, Pharmacy and materia medica, RS1-441, Chemistry, QD1-999
Abstract: A series of new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds were designed, synthesized, and evaluated in vitro against two parasites (Plasmodium falciparum and Leishmania donovani). The biological results showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new aza polyaromatic derivatives was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1m was found as one of the most potent and promising antimalarial candidates with a ratio of cytotoxic to antiprotozoal activities of 83.67 against the P. falciparum CQ-sensitive strain 3D7. In addition, derivative 1r was also identified as the most interesting antimalarial compound with a selectivity index (SI) of 17.28 on the W2 P. falciparum CQ-resistant strain. It was previously described that the telomeres of P. falciparum could be considered as potential targets of these kinds of aza heterocycles; thus, the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes was measured through a FRET melting assay.
Published: 2023
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3. Role of the European Pharmacist in the Implementation of the Latest WHO Guidelines for Malaria

Author: Anita Cohen
Subjects: pharmacist, pharmaceutical advice, pharmaceutical analysis, public health promotion, WHO guidelines for malaria, personal protection measures, Medicine
Abstract: Following the publication a few months ago of the new WHO guidelines for malaria, the European pharmacist, even out of endemic areas, as a health care professional and advisor, has a major role to play in their effective implementation and in the interest of public health. The pharmacist is central in the health care system to ensure the correct application of these recommendations and to perform a decisive role in the prevention of malaria infections, both in the adapted pharmaceutical advice on personal protection against biting vector insects on the one hand, and in the pharmaceutical analysis and recommendations concerning antimalarial chemoprophylaxis prescriptions on the other hand. Physicians and pharmacist biologists, as well as hospital pharmacists, are also important for the analysis and treatment of effective malaria cases, particularly in the management of the diagnostic and therapeutic emergency that a P. falciparum infection represents.
Published: 2023
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4. Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives

Author: Jean Guillon, Anita Cohen, Clotilde Boudot, Alessandra Valle, Vittoria Milano, Rabindra Nath Das, Aurore Guédin, Stéphane Moreau, Luisa Ronga, Solène Savrimoutou, Maxime Demourgues, Elodie Reviriego, Sandra Rubio, Sandie Ferriez, Patrice Agnamey, Cécile Pauc, Serge Moukha, Pascale Dozolme, Sophie Da Nascimento, Pierre Laumaillé, Anne Bouchut, Nadine Azas, Jean-Louis Mergny, Catherine Mullié, Pascal Sonnet, and Bertrand Courtioux
Subjects: antimalarial activity, quinoline-like derivatives, antitrypanosomal activity, antileishmanial activity, g-quadruplex, Therapeutics. Pharmacology, RM1-950
Abstract: A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays.
Published: 2020
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5. A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites

Author: Henriette Bosson-Vanga, Nicolas Primas, Jean-François Franetich, Catherine Lavazec, Lina Gomez, Kutub Ashraf, Maurel Tefit, Valérie Soulard, Nathalie Dereuddre-Bosquet, Roger Le Grand, Mélanie Donnette, Romain Mustière, Nadia Amanzougaghene, Shahin Tajeri, Peggy Suzanne, Aurélie Malzert-Fréon, Sylvain Rault, Patrice Vanelle, Sébastien Hutter, Anita Cohen, Georges Snounou, Pierre Roques, Nadine Azas, Prisca Lagardère, Vincent Lisowski, Nicolas Masurier, Michel Nguyen, Lucie Paloque, Françoise Benoit-Vical, Pierre Verhaeghe, and Dominique Mazier
Subjects: antimalarials, 2-amino-6-phenyl-thienopyrimidin-4(3H)-one, multistage activity, artemisinin resistance, Microbiology, QR1-502
Abstract: ABSTRACT Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. For decades, the research for novel antimalarials focused on the high-throughput screening of molecules that only targeted the asexual blood stages. In a search for new effective compounds presenting a triple action against erythrocytic and liver stages in addition to the ability to block the transmission of the disease via the mosquito vector, 2-amino-thienopyrimidinone derivatives were synthesized and tested for their antimalarial activity. One molecule, named gamhepathiopine (denoted as “M1” herein), was active at submicromolar concentrations against both erythrocytic (50% effective concentration [EC50] = 0.045 μM) and liver (EC50 = 0.45 μM) forms of Plasmodium falciparum. Furthermore, gamhepathiopine efficiently blocked the development of the sporogonic cycle in the mosquito vector by inhibiting the exflagellation step. Moreover, M1 was active against artemisinin-resistant forms (EC50 = 0.227 μM), especially at the quiescent stage. Nevertheless, in mice, M1 showed modest activity due to its rapid metabolization by P450 cytochromes into inactive derivatives, calling for the development of new parent compounds with improved metabolic stability and longer half-lives. These results highlight the thienopyrimidinone scaffold as a novel antiplasmodial chemotype of great interest to search for new drug candidates displaying multistage activity and an original mechanism of action with the potential to be used in combination therapies for malaria elimination in the context of artemisinin resistance. IMPORTANCE This work reports a new chemical structure that (i) displays activity against the human malaria parasite Plasmodium falciparum at 3 stages of the parasitic cycle (blood stage, hepatic stage, and sexual stages), (ii) remains active against parasites that are resistant to the first-line treatment recommended by the World Health Organization (WHO) for the treatment of severe malaria (artemisinins), and (iii) reduces transmission of the parasite to the mosquito vector in a mouse model. This new molecule family could open the way to the conception of novel antimalarial drugs with an original multistage mechanism of action to fight against Plasmodium drug resistance and block interhuman transmission of malaria.
Published: 2021
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6. Design, Synthesis, and Antiprotozoal Evaluation of New Promising 2,9-Bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline Derivatives, a Potential Alternative Scaffold to Drug Efflux

Author: Jean Guillon, Anita Cohen, Clotilde Boudot, Sarah Monic, Solène Savrimoutou, Stéphane Moreau, Sandra Albenque-Rubio, Camille Lafon-Schmaltz, Alexandra Dassonville-Klimpt, Jean-Louis Mergny, Luisa Ronga, Mikel Bernabeu de Maria, Jeremy Lamarche, Cristina Dal Lago, Eric Largy, Valérie Gabelica, Serge Moukha, Pascale Dozolme, Patrice Agnamey, Nadine Azas, Catherine Mullié, Bertrand Courtioux, and Pascal Sonnet
Subjects: antimalarial activity, phenanthroline, G-quadruplex, antileishmanial activity, antitrypanosomal activity, Medicine
Abstract: A series of novel 2,9-bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline derivatives was designed, synthesized, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei). Pharmacological results showed antiprotozoal activity with IC50 values in the sub and μM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The substituted diphenylphenanthroline 1l was identified as the most potent antimalarial derivative with a ratio of cytotoxic to antiparasitic activities of 505.7 against the P. falciparum CQ-resistant strain W2. Against the promastigote forms of L. donovani, the phenanthrolines 1h, 1j, 1n and 1o were the most active with IC50 from 2.52 to 4.50 μM. The phenanthroline derivative 1o was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 91 on T. brucei brucei strain. FRET melting and native mass spectrometry experiments evidenced that the nitrogen heterocyclic derivatives bind the telomeric G-quadruplexes of P. falciparum and Trypanosoma. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma could be considered to be possible targets of this kind of nitrogen heterocyclic derivatives, their potential ability to stabilize the parasitic telomeric G-quadruplexes have been determined through the FRET melting assay and by native mass spectrometry.
Published: 2022
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7. Challenges and Tools for In Vitro Leishmania Exploratory Screening in the Drug Development Process: An Updated Review

Author: Anita Cohen and Nadine Azas
Subjects: zoonotic visceral leishmaniasis, in vitro exploratory antileishmanial screening, cell viability, fluorescence, bioluminescence, RNA interference, Medicine
Abstract: Leishmaniases are a group of vector-borne diseases caused by infection with the protozoan parasites Leishmania spp. Some of them, such as Mediterranean visceral leishmaniasis, are zoonotic diseases transmitted from vertebrate to vertebrate by a hematophagous insect, the sand fly. As there is an endemic in more than 90 countries worldwide, this complex and major health problem has different clinical forms depending on the parasite species involved, with the visceral form being the most worrying since it is fatal when left untreated. Nevertheless, currently available antileishmanial therapies are significantly limited (low efficacy, toxicity, adverse side effects, drug-resistance, length of treatment, and cost), so there is an urgent need to discover new compounds with antileishmanial activity, which are ideally inexpensive and orally administrable with few side effects and a novel mechanism of action. Therefore, various powerful approaches were recently applied in many interesting antileishmanial drug development programs. The objective of this review is to focus on the very first step in developing a potential drug and to identify the exploratory methods currently used to screen in vitro hit compounds and the challenges involved, particularly in terms of harmonizing the results of work carried out by different research teams. This review also aims to identify innovative screening tools and methods for more extensive use in the drug development process.
Published: 2021
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8. 2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

Author: Dyhia Amrane, Christophe-Sébastien Arnold, Sébastien Hutter, Julen Sanz-Serrano, Miguel Collia, Amaya Azqueta, Lucie Paloque, Anita Cohen, Nadia Amanzougaghene, Shahin Tajeri, Jean-François Franetich, Dominique Mazier, Françoise Benoit-Vical, Pierre Verhaeghe, Nadine Azas, Patrice Vanelle, Cyrille Botté, and Nicolas Primas
Subjects: quinoxaline, trichloromethyl goup, Plasmodium falciparum, structure-activity relationships, apicoplast, Medicine, Pharmacy and materia medica, RS1-441
Abstract: The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure–activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 µM and a HepG2 CC50 value of 32 µM (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site.
Published: 2021
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9. Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives

Author: Jean Guillon, Anita Cohen, Nassima Meriem Gueddouda, Rabindra Nath Das, Stéphane Moreau, Luisa Ronga, Solène Savrimoutou, Louise Basmaciyan, Alix Monnier, Myriam Monget, Sandra Rubio, Timothée Garnerin, Nadine Azas, Jean-Louis Mergny, Catherine Mullié, and Pascal Sonnet
Subjects: Antimalarial activity, bis-pyrrolo[1,2-a]quinoxaline, Plasmodium falciparum, G-quadruplex, antileishmanial activity, Therapeutics. Pharmacology, RM1-950
Abstract: Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC50 in the μM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure–activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds.
Published: 2017
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10. Synthesis of 1H-3-{4-[(3-Dimethylaminopropyl)aminomethyl]phenyl}-2-phenylindole and Evaluation of Its Antiprotozoal Activity

Author: Jean Guillon, Clotilde Boudot, Anita Cohen, Solène Savrimoutou, Sandra Rubio, Vittoria Milano, Mathieu Marchivie, Nadine Azas, Catherine Mullié, Pascal Sonnet, and Bertrand Courtioux
Subjects: indole derivative, antimalarial activity, antileishmanial activity, antitrypanosomal activity, Inorganic chemistry, QD146-197
Abstract: 1H-3-{4-[(3-Dimethylaminopropyl)aminomethyl]phenyl}-2-phenylindole was synthesized via a multi-step pathway starting from 2-iodoaniline. Structure characterization of this new indole compound was achieved by 1H-NMR, 13C-NMR and ESI-MS spectral analysis. The title compound was screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the μM range.
Published: 2019
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11. Synthesis and Promising in Vitro Antiproliferative Activity of Sulfones of a 5-Nitrothiazole Series

Author: Nadine Azas, Patrice Vanelle, Pascal Rathelot, Maxime D. Crozet, and Anita Cohen
Subjects: 5-nitrothiazole, sulfones, microwave irradiation, in vitro antiproliferative, HepG2 cell line, activity cellular specificity, Organic chemistry, QD241-441
Abstract: The synthesis in water of new sulfone derivatives under microwave irradiation is described. This eco-friendly process leads to the expected products in good yields by reaction of various substituted sulfinates (commercially available or obtained by reduction of the corresponding sulfonyl chlorides) with 4-chloromethyl-2-methyl-5-nitro-1,3-thiazole. In order to evaluate the antiproliferative effect of these compounds, several sulfone derivatives are also dichlorinated on the Cα next to the sulfonyl group. An evaluation on different cancer cell lines reveals promising selective in vitro antiproliferative activity toward HepG2 human cell lines by dihydrogenated sulfones, suggesting further research should be to explore their anticancer potential in the treatment of liver cancer.
Published: 2012
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12. A New Synthetic Route to Original Sulfonamide Derivatives in 2-Trichloromethylquinazoline Series: A Structure-Activity Relationship Study of Antiplasmodial Activity

Author: Nadine Azas, Sylvain Rault, Pascal Rathelot, Sébastien Hutter, Aurélien Dumètre, Charline Kieffer, Anita Cohen, Pierre Verhaeghe, Nicolas Primas, and Patrice Vanelle
Subjects: quinazoline, trichloromethyl group, sulfonamide, microwaves, antiplasmodial activity, Organic chemistry, QD241-441
Abstract: We report herein a simple and efficient two-step synthetic approach to new 2-trichloromethylquinazolines possessing a variously substituted sulfonamide group at position 4 used to prepare new quinazolines with antiparasitic properties. Thus, an original series of 20 derivatives was synthesized, which proved to be less-toxic than previously synthesized hits on the human HepG2 cell line, but did not display significant antiplasmodial activity. A brief Structure-Activity Relationship (SAR) evaluation shows that a more restricted conformational freedom is probably necessary for providing antiplasmodial activity.
Published: 2012
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13. Synthesis and Antiprotozoal Evaluation of New 2,9-bis[(pyridinylalkylaminomethyl) phenyl]-1,10-Phenanthroline Derivatives by Targeting G-quadruplex, an Interesting Pharmacophore Against Drug Efflux

Author: Jean Guillon, Anita Cohen, Sarah Monic, Clotilde Boudot, Solène Savrimoutou, Sandra Albenque-Rubio, Stéphane Moreau, Alexandra Dassonville-Klimpt, Jean-Louis Mergny, Luisa Ronga, Mikel Bernabeu de Maria, Nikita Tyurin-Schmitt, Paul Parrens, Adrien Labarthe, Valentin Gomez, Serge Moukha, Pascale Dozolme, Nadine Azas, Valérie Gabelica, Patrice Agnamey, Céline Damiani, Anne Totet, Catherine Mullié, Bertrand Courtioux, and Pascal Sonnet
Subjects: General Materials Science
Published: 2023
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14. Table S3 from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author: Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon
Abstract: PFS6 and PFS12 depending of the in intention-to-treat or per protocole analyses as investigator or central review analyses.
Published: 2023
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15. Figure S4 from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author: Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon
Abstract: Study of correlation between SSTR2A receptor expression and growth rate (GR) before and under treatment as with progression. No significant correlation was observed. Immunohistochemical detection of SSTR2A protein was performed on 5 µm thick formalin fixed paraffin embedded (FFPE) tissue sections with Ventana Benchmark XT. The monoclonal SSTR2A antibody (clone UMB1, Abcam) was used at 1/4000 dilution.
Published: 2023
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16. Data from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author: Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon
Abstract: Purpose:Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas.Patients and Methods:Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety.Results:A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003).Conclusions:The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.
Published: 2023
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17. Design, Synthesis, and Antiprotozoal Evaluation of New Promising 2,9-Bis[(substituted-aminomethyl)]-4,7-phenyl-1,10phenanthroline Derivatives, a Potential Alternative Scaffold to Drug Efflux

Author: Jean Guillon, Anita Cohen, Clotilde Boudot, Sarah Monic, Solène Savrimoutou, Stéphane Moreau, Sandra Albenque-Rubio, Camille Lafon-Schmaltz, Alexandra Dassonville-Klimpt, Jean-Louis Mergny, Luisa Ronga, Mikel Bernabeu de Maria, Jeremy Lamarche, Cristina Dal Lago, Eric Largy, Valérie Gabelica, Serge Moukha, Pascale Dozolme, Patrice Agnamey, Nadine Azas, Catherine Mullié, Bertrand Courtioux, Pascal Sonnet, Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Laboratoire d'Optique et Biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Polytechnique de Paris (IP Paris), Institut des sciences analytiques et de physico-chimie pour l'environnement et les materiaux (IPREM), Université de Pau et des Pays de l'Adour (UPPA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Environnement, Santé/Stic (E2S), Université de Bourgogne (UB), Université de Pau et des Pays de l'Adour (UPPA), Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Mergny, Jean-Louis, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Unité de recherche Mycologie et Sécurité des Aliments (MycSA), and Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Microbiology (medical), General Immunology and Microbiology, G-quadruplex, antimalarial activity, phenanthroline, antileishmanial activity, antitrypanosomal activity, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Infectious Diseases, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Immunology and Allergy, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]
Abstract: International audience; A series of novel 2,9-bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline derivatives was designed, synthesized, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei). Pharmacological results showed antiprotozoal activity with IC50 values in the sub and μM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The substituted diphenylphenanthroline 1l was identified as the most potent antimalarial derivative with a ratio of cytotoxic to antiparasitic activities of 505.7 against the P. falciparum CQ-resistant strain W2. Against the promastigote forms of L. donovani, the phenanthrolines 1h, 1j, 1n and 1o were the most active with IC50 from 2.52 to 4.50 μM. The phenanthroline derivative 1o was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 91 on T. brucei brucei strain. FRET melting and native mass spectrometry experiments evidenced that the nitrogen heterocyclic derivatives bind the telomeric G-quadruplexes of P. falciparum and Trypanosoma. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma could be considered to be possible targets of this kind of nitrogen heterocyclic derivatives, their potential ability to stabilize the parasitic telomeric G-quadruplexes have been determined through the FRET melting assay and by native mass spectrometry.
Published: 2022
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18. Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity

Author: Catherine Mullié, Mathieu Marchivie, Patrice Agnamey, Anne Totet, Bruno Pradines, Anita Cohen, Alexandra Dassonville-Klimpt, Jérôme Dormoi, Jean Guillon, Nadine Azas, Céline Damiani, Pascal Sonnet, Jeremy Schneider, N. Taudon, C. Tisnerat, Toulin, Stéphane, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Biomédicale des Armées (IRBA), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre National de Référence du Paludisme [IRBA, Marseille] (CNRP), Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), The authors would like to thank Philippe Grellier, department RDDM at Muséum National d’Histoire Naturelle (Paris, France), for providing generously the 3D7 and W2 P. falciparum strains and Sylvie Klieber and Alain Pellet, Sanofi R et D France, for in vitro ADMET study (Papp, hERG activity, microsomal and hepatic clearance and CY3A4 activity)., Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), and ANR-21-ASM1-0003,MORHOC'H 2,Modélisation de l'interaction de la houle et d'un courant inhomogène en zone côtière(2021)
Subjects: Plasmodium falciparum, P. falciparum, mefloquine analogs, Cell Line, 03 medical and health sciences, Antimalarials, Mice, Structure-Activity Relationship, Cricetulus, Pharmacokinetics, Parasitic Sensitivity Tests, In vivo, Drug Discovery, Ic50 values, Animals, Humans, antimalarial drug resistance, aminoalcohol quinolines, 030304 developmental biology, Pharmacology, 0303 health sciences, Mice, Inbred BALB C, [CHIM.MATE] Chemical Sciences/Material chemistry, Dose-Response Relationship, Drug, Molecular Structure, 030306 microbiology, Chemistry, Organic Chemistry, General Medicine, [CHIM.MATE]Chemical Sciences/Material chemistry, Combinatorial chemistry, Amino Alcohols, In vitro, Ether-A-Go-Go Potassium Channels, 3. Good health, Malaria, Design synthesis, Novel agents, Drug Design, Microsomes, Liver, Quinolines, Female, Selectivity
Abstract: International audience; Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100. 17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties
Published: 2022
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19. A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites

Author: Sylvain Rault, Maurel Tefit, Vincent Lisowski, Patrice Vanelle, Nicolas Primas, Jean-François Franetich, Dominique Mazier, Lucie Paloque, Pierre Roques, Sébastien Hutter, Georges Snounou, Françoise Benoit-Vical, Michel Nguyen, Prisca Lagardère, Valérie Soulard, Nathalie Dereuddre-Bosquet, Pierre Verhaeghe, Anita Cohen, Nicolas Masurier, Roger Le Grand, Nadia Amanzougaghene, Nadine Azas, Mélanie Donnette, Kutub Ashraf, Catherine Lavazec, Aurélie Malzert-Fréon, Lina Gomez, Henriette Bosson-Vanga, Shahin Tajeri, Romain Mustière, Peggy Suzanne, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Félix Houphouët-Boigny (UFHB), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Casselardit - Junod, Fondation pour la Recherche Médicale (FRM Palukill DMC20181039565), Centre National de la Recherche Scientifique (CNRS), ANR-18-CE18-0009,plasmodrug,Développement d'un nouvel antipaludique ciblant plusieurs étapes du cycle de Plasmodium(2018), ANR-17-CE13-0025,IMHyp,Recherches sur l'Hypnozoïte du Paludisme(2017), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Gulli, Marie-Hélène, APPEL À PROJETS GÉNÉRIQUE 2018 - Développement d'un nouvel antipaludique ciblant plusieurs étapes du cycle de Plasmodium - - plasmodrug2018 - ANR-18-CE18-0009 - AAPG2018 - VALID, Recherches sur l'Hypnozoïte du Paludisme - - IMHyp2017 - ANR-17-CE13-0025 - AAPG2017 - VALID, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Infrastructures - Infrastructure nationale pour la modélisation des maladies infectieuses humaines - - IDMIT2011 - ANR-11-INBS-0008 - INBS - VALID, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Physiology, Drug Resistance, Drug resistance, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Plasmodium, Madin Darby Canine Kidney Cells, Mice, Multistage activity, Artemisinin, Malaria, Falciparum, 0303 health sciences, Mice, Inbred BALB C, Ecology, biology, Hep G2 Cells, 2-amino-6-phenyl-thienopyrimidin-4(3H)-one, Artemisinins, QR1-502, 3. Good health, Infectious Diseases, Liver, Artemisinin resistance, Female, medicine.symptom, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, medicine.drug, Plasmodium cynomolgi, Research Article, Microbiology (medical), [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Plasmodium falciparum, Context (language use), Pyrimidinones, Microbiology, 03 medical and health sciences, Antimalarials, Dogs, Cell Line, Tumor, parasitic diseases, Genetics, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, 030304 developmental biology, General Immunology and Microbiology, 030306 microbiology, Cell Biology, Plasmodium yoelii, medicine.disease, biology.organism_classification, Virology, Disease Models, Animal, Macaca fascicularis, Mechanism of action, Vector (epidemiology), Malaria
Abstract: International audience; Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. For decades, the research for novel antimalarials focused on the high-throughput screening of molecules that only targeted the asexual blood stages. In a search for new effective compounds presenting a triple action against erythrocytic and liver stages in addition to the ability to block the transmission of the disease via the mosquito vector, 2-amino-thienopyrimidinone derivatives were synthesized and tested for their antimalarial activity. One molecule, named gamhepathiopine (denoted as “M1” herein), was active at submicromolar concentrations against both erythrocytic (50% effective concentration [EC50] = 0.045 μM) and liver (EC50 = 0.45 μM) forms of Plasmodium falciparum. Furthermore, gamhepathiopine efficiently blocked the development of the sporogonic cycle in the mosquito vector by inhibiting the exflagellation step. Moreover, M1 was active against artemisinin-resistant forms (EC50 = 0.227 μM), especially at the quiescent stage. Nevertheless, in mice, M1 showed modest activity due to its rapid metabolization by P450 cytochromes into inactive derivatives, calling for the development of new parent compounds with improved metabolic stability and longer half-lives. These results highlight the thienopyrimidinone scaffold as a novel antiplasmodial chemotype of great interest to search for new drug candidates displaying multistage activity and an original mechanism of action with the potential to be used in combination therapies for malaria elimination in the context of artemisinin resistance.IMPORTANCE This work reports a new chemical structure that (i) displays activity against the human malaria parasite Plasmodium falciparum at 3 stages of the parasitic cycle (blood stage, hepatic stage, and sexual stages), (ii) remains active against parasites that are resistant to the first-line treatment recommended by the World Health Organization (WHO) for the treatment of severe malaria (artemisinins), and (iii) reduces transmission of the parasite to the mosquito vector in a mouse model. This new molecule family could open the way to the conception of novel antimalarial drugs with an original multistage mechanism of action to fight against Plasmodium drug resistance and block interhuman transmission of malaria.
Published: 2021
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20. Synthesis and in vitro evaluation of new 5-substituted 6-nitroimidazooxazoles as antikinetoplastid agents

Author: Nadine Azas, Roberto Docampo, Nuria Waddington Negrao, Fanny Mathias, Anita Cohen, Patrice Vanelle, Maxime D. Crozet, Youssef Kabri, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), University of Georgia [USA], and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: Trypanosoma, Trypanosoma cruzi, Antiprotozoal Agents, Substituent, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Parasitic Sensitivity Tests, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Drug Discovery, medicine, Nitroheterocycles, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Oxazoles, 030304 developmental biology, Oxazole, Imidazo[2, Pharmacology, Leishmania, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Aryl, Organic Chemistry, 1-b]oxazole, General Medicine, Reference drug, Combinatorial chemistry, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, In vitro, 0104 chemical sciences, 3. Good health, chemistry, Nitroimidazoles, Benznidazole, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Leishmania donovani, medicine.drug, Pallado-catalyzed cross-coupling reaction
Abstract: International audience; In continuation of our pharmacomodulation work on the nitroimidazooxazole series, we report the synthesis of new 5-substituted 6-nitroimidazooxazole derivatives. Our aim was to evaluate how func-tionalization of the 5-position of the 6-nitroimidazooxazole scaffold affects antileishmanial and anti-trypanosomal in vitro activities. Twenty-one original compounds were synthesized and evaluated for their in vitro antileishmanial (L. donovani) and antitrypanosomal (T. cruzi) properties. Pallado-catalyzed cross-coupling reactions were used to introduce an aryl or ethynyl aryl substituent in 5-position from a 5-brominated-6-nitroimidazooxazole starting product. Unfortunately, the first series of compounds bearing an aryl group in 5-position presented limited in vitro activities against L. donovani and T. cruzi, with IC 50 > 10 mM (vs 0.18 mM and 2.31 mM for the reference drugs amphotericin B and benznidazole respectively). Interestingly, the second series of compounds bearing an ethynyl aryl substituent in 5-position showed more promising, particularly against T. cruzi. Compounds 6a, 6b, 6c, 6g and 6h had better activity than the reference drug benznidazole (0.92 mM IC 50 2.18 mM vs IC 50 ¼ 2.31 mM), whereas the non-functionalized 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b]oxazole 2 was not active against T. cruzi (IC 50 > 10 mM).
Published: 2020
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21. Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author: Olivier Chinot, Marc Sanson, Hadrien Peyrière, Emeline Tabouret, Thomas Graillon, Ahmed Idbaih, Stéphane Honoré, Anita Cohen, Matthieu Peyre, Dominique Figarella-Branger, Pierre-Hugues Roche, Noémie Basset, Mohamed Boucekine, Maryline Barrie, Henry Dufour, Michel Kalamarides, Chantal Campello, Didier Autran, Anne Barlier, Catherine Roche, Karine Baumstarck, Stéphane Fuentes, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service de Neurochirurgie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Département de neurochirurgie, Hôpital Nord [CHU - APHM], Département de Neurochirurgie [CHU Timone], SERVICE DE NEUROONCOLOGIE MARSEILLE, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Assistance Publique-Hôpitaux de Marseille (AP-HM), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix-Marseille Université - Faculté de médecine (AMU MED), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Hôpital Beaujon [AP-HP]-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU)
Subjects: Male, Cancer Research, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Octreotide, Gastroenterology, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Meningeal Neoplasms, Prospective Studies, Receptors, Somatostatin, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, TOR Serine-Threonine Kinases, Middle Aged, 3. Good health, Tumor Burden, Survival Rate, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Patient Safety, Meningioma, medicine.drug, Recurrent Meningioma, Adult, medicine.medical_specialty, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, otorhinolaryngologic diseases, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Everolimus, neoplasms, Survival rate, Aged, business.industry, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, nervous system diseases, Clinical trial, Radiation therapy, Neoplasm Recurrence, Local, business, 030217 neurology & neurosurgery
Abstract: Purpose: Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas. Patients and Methods: Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety. Results: A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003). Conclusions: The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.
Published: 2019
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22. Synthesis of 1H-3-{4-[(3-Dimethylaminopropyl)aminomethyl]phenyl}-2-phenylindole and Evaluation of Its Antiprotozoal Activity

Author: Mathieu Marchivie, Anita Cohen, Jean Guillon, Catherine Mullié, Bertrand Courtioux, Clotilde Boudot, Vittoria Milano, Sandra Rubio, Pascal Sonnet, Solène Savrimoutou, Nadine Azas, Régulations Naturelles et Artificielles (ARNA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Glycochimie, des Antimicrobiens et des Agro-ressources - UMR CNRS 7378 (LG2A ), Université de Picardie Jules Verne (UPJV)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Université de Limoges (UNILIM), and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA)
Subjects: Indole Compound, medicine.drug_class, Stereochemistry, Antiparasitic, Leishmania donovani, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Trypanosoma brucei, 01 natural sciences, Biochemistry, antimalarial activity, 03 medical and health sciences, parasitic diseases, medicine, lcsh:Inorganic chemistry, antileishmanial activity, Physical and Theoretical Chemistry, indole derivative, antitrypanosomal activity, 0303 health sciences, biology, 010405 organic chemistry, 030306 microbiology, Chemistry, Organic Chemistry, Plasmodium falciparum, biology.organism_classification, In vitro, lcsh:QD146-197, 0104 chemical sciences, 3. Good health, Antiprotozoal, 2-Phenylindole
Abstract: 1H-3-{4-[(3-Dimethylaminopropyl)aminomethyl]phenyl}-2-phenylindole was synthesized via a multi-step pathway starting from 2-iodoaniline. Structure characterization of this new indole compound was achieved by 1H-NMR, 13C-NMR and ESI-MS spectral analysis. The title compound was screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the μM range.
Published: 2019
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23. Nongenotoxic 3-Nitroimidazo[1,2

Author: Cyril, Fersing, Louise, Basmaciyan, Clotilde, Boudot, Julien, Pedron, Sébastien, Hutter, Anita, Cohen, Caroline, Castera-Ducros, Nicolas, Primas, Michèle, Laget, Magali, Casanova, Sandra, Bourgeade-Delmas, Mélanie, Piednoel, Alix, Sournia-Saquet, Valère, Belle Mbou, Bertrand, Courtioux, Élisa, Boutet-Robinet, Marc, Since, Rachel, Milne, Susan, Wyllie, Alan H, Fairlamb, Alexis, Valentin, Pascal, Rathelot, Pierre, Verhaeghe, Patrice, Vanelle, and Nadine, Azas
Subjects: parasitic diseases
Abstract: [Image: see text] Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC(50) > 100 μM) alongside good antileishmanial activities (IC(50) = 1–2.1 μM) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC(50) = 1.3–2.2 μM) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC(50) = 0.6 to 13.3 μM). Molecule 5, presenting a low reduction potential (E° = −0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies.
Published: 2018

24. Synthesis and Antimalarial Activity of New Enantiopure Aminoalcoholpyrrolo[1,2-a]quinoxalines

Author: Pascal Sonnet, Jean Guillon, Jeremy Schneider, Patrice Agnamey, Catherine Mullié, Solène Savrimoutou, Stéphane Moreau, Anita Cohen, Sébastien Hutter, Alexandra Dassonville-Klimpt, Guillaume Bentzinger, Nadine Azas, Alexia Jonet, Nicolas Taudon, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche Biomédicale des Armées (IRBA)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA)
Subjects: Stereochemistry, [SDV]Life Sciences [q-bio], Plasmodium falciparum, CHO Cells, 010402 general chemistry, 01 natural sciences, chemistry.chemical_compound, Antimalarials, Quinoxaline, Cricetulus, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cell Line, Tumor, Quinoxalines, Drug Discovery, parasitic diseases, [CHIM]Chemical Sciences, Animals, Humans, Pyrroles, biology, 010405 organic chemistry, Quinoline, Enantioselective synthesis, Chloroquine, Stereoisomerism, biology.organism_classification, Amino Alcohols, 0104 chemical sciences, 3. Good health, Mefloquine, Enantiopure drug, chemistry, Enantiomer, Selectivity, Sharpless asymmetric dihydroxylation
Abstract: International audience; Background: We prepared a novel series of enantiopure mefloquine analogues with pyrrolo[1,2-a]quinoxaline core in order to fight Plasmodium falciparum resistant strain. Objectives: To observe the influence of pyrrolo[1,2-a]quinoxaline core versus quinoline core on the antimalarial activity. Method: Four enantiopure aminoalcoholpyrrolo[1,2-a]quinoxalines 2 were synthetized via Sharpless asymmetric dihydroxylation reaction in eight steps. Their antimalarial activity was evaluated on two Plasmodium falciparum strains 3D7 and W2 with a SYBR Green I fluorescence-based method and their cytotoxicity was measured on four cell lines HepG2, THP-1, CHO and HFF. Results: IC50 values of the four compounds 2 were close to the micromolar against the two P. falciparum strains. They were more active against P. falciparum strain W2 vs. P. falciparum strain 3D7. (R)-enantiomers were always more active than their (S)-counterpart whatever the strain. Selectivity indexes of compounds 2 were lower than 100. Conclusion: A novel series of enantiopure aminoalcohols with pyrrolo[1,2-a]quinoxaline core were synthesized in eight steps. They displayed IC50 values close to the micromolar against two P. falciparum strains 3D7 and W2. Although, In this series, 2,8-bistrifluoromethylquinoline was a best core than pyrrolo[1,2-a]quinoxaline for an optimal antimalarial activity, the pyrroloquinoxaline 2b showed an interesting antimalarial activity.
Published: 2018
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25. 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a] pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

Author: Maxime D. Crozet, Alan H. Fairlamb, Geneviève Pratviel, Alexis Valentin, Pascal Rathelot, Alix Sournia-Saquet, Clotilde Boudot, Anita Cohen, Patrice Vanelle, Julien Pedron, Jean-Luc Stigliani, Sandra Bourgeade-Delmas, Susan Wyllie, Pierre Verhaeghe, Nadine Azas, Caroline Castera-Ducros, Cyril Fersing, Alain Moreau, Sébastien Hutter, Nicolas Primas, Bertrand Courtioux, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Department of Biochemistry, Medical Sciences Institute, Dundee University, Dundee, Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), and Université de Toulouse (UT)
Subjects: Models, Molecular, 0301 basic medicine, SARs, Redox potentials, HepG2 cytotoxicity, Crystallography, X-Ray, MESH: Parasitic Sensitivity Tests, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, MESH: Structure-Activity Relationship, Parasitic Sensitivity Tests, In vitro activity, Drug Discovery, Nitroheterocycles, Moiety, MESH: Trypanocidal Agents, Imidazo[1, Leishmania, 2-a]pyridine, Molecular Structure, MESH: Drug Screening Assays, Antitumor, Hep G2 Cells, General Medicine, Trypanocidal Agents, 3. Good health, MESH: Nitroreductases, MESH: Cell Survival, Imidazo[1,2-a]pyridine, Pharmacophore, MESH: Models, Molecular, Trypanosoma, MESH: Cell Line, Tumor, Cell Survival, Stereochemistry, Antiparasitic, medicine.drug_class, Trypanosoma brucei brucei, 030106 microbiology, MESH: Molecular Structure, Substituent, Antineoplastic Agents, MESH: Hep G2 Cells, Article, Structure-Activity Relationship, 03 medical and health sciences, Cell Line, Tumor, MESH: Cell Proliferation, medicine, Humans, Amastigote, Cell Proliferation, Pharmacology, MESH: Humans, MESH: Leishmania donovani, Dose-Response Relationship, Drug, Aryl, Organic Chemistry, MESH: Trypanosoma brucei brucei, Nitroreductases, MESH: Crystallography, X-Ray, 030104 developmental biology, chemistry, Nitro, Suzuki-Miyaura cross-coupling reaction, MESH: Antineoplastic Agents, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Drug Screening Assays, Antitumor, Leishmania donovani, Fexinidazole
Abstract: International audience; Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.
Published: 2018
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26. Design, synthesis, and antiprotozoal evaluation of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives

Author: Sacha Mestanier, Alexandra Dassonville-Klimpt, Jean-Louis Mergny, Camille Tisnerat, Luisa Ronga, Bertrand Courtioux, Sophia Amaziane, Catherine Mullié, Stéphane Moreau, Nadine Azas, Clotilde Boudot, Rabindra Nath Das, Jean Guillon, Solène Savrimoutou, Pascal Sonnet, Anita Cohen, Sandra Rubio, Louise Basmaciyan, Nassima Meriem Gueddouda, Régulations Naturelles et Artificielles (ARNA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Laboratoire des Glucides (LG), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Picardie Jules Verne (UPJV), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, and Université de Picardie Jules Verne (UPJV)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Antiparasitic, medicine.drug_class, Stereochemistry, Cell Survival, Phenanthroline, Plasmodium falciparum, Trypanosoma brucei brucei, Leishmania donovani, Antiprotozoal Agents, Trypanosoma brucei, Ligands, 01 natural sciences, Biochemistry, antimalarial activity, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, parasitic diseases, medicine, Humans, Transition Temperature, antileishmanial activity, Cytotoxicity, antitrypanosomal activity, Pharmacology, biology, G-quadruplex, Organic Chemistry, Hep G2 Cells, biology.organism_classification, In vitro, 0104 chemical sciences, 3. Good health, phenanthroline, G-Quadruplexes, 010404 medicinal & biomolecular chemistry, 030104 developmental biology, chemistry, Drug Design, Antiprotozoal, Molecular Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Phenanthrolines
Abstract: International audience; A series of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the μm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic-to-antiparasitic activities of 107 and 39 against a chloroquine-sensitive and a chloroquine-resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G-quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence.
Published: 2017
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27. Design, synthesis and biological evaluation of novel 4-alkapolyenylpyrrolo[1,2-a]quinoxalines as antileishmanial agents – Part III

Author: Luisa Ronga, Noël Pinaud, Patrice Le Pape, Philippe Vincendeau, Solène Savrimoutou, Patrice Agnamey, Claire Soum, Sylvie Daulouède, Sébastien Hutter, Nadine Azas, Anita Cohen, Jean Guillon, Catherine Mullié, Natacha Farvacques, Fabrice Pagniez, Pascal Sonnet, Marco Del Favero, Université de Bordeaux (UB), Régulations Naturelles et Artificielles (ARNA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Cibles et Médicaments des Infections et de l'Immunité (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Université de Bordeaux, ARNA Laboratory (U869), Laboratoire de Glycochimie, des Antimicrobiens et des Agro-ressources - UMR CNRS 7378 (LG2A ), Université de Picardie Jules Verne (UPJV)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux Ségalen [Bordeaux 2], Laboratoire de parasitologie et de mycologie médicales [CHU Amiens], CHU Amiens-Picardie, Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie
Subjects: Suzuki reaction, Antiparasitic, medicine.drug_class, Stereochemistry, Plasmodium falciparum, Trypanosoma brucei brucei, Antitrypanosomal activity, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Trypanosoma brucei, Antimalarial activity, Synthesis, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Quinoxaline, Parasitic Sensitivity Tests, Pyrrolo[1, Quinoxalines, 2-a] quinoxaline, parasitic diseases, Drug Discovery, medicine, Animals, Humans, [CHIM]Chemical Sciences, Cytotoxicity, Cell Proliferation, Leishmania, Pharmacology, Dose-Response Relationship, Drug, Molecular Structure, biology, Chemistry, Macrophages, Alkaloid, Organic Chemistry, Hep G2 Cells, General Medicine, Antileishmanial activity, biology.organism_classification, Trypanocidal Agents, Combinatorial chemistry, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Trypanosomiasis, African, Drug Design, Antiprotozoal, Female
Abstract: cited By 8; International audience; A series of new 4-alkapolyenylpyrrolo[1,2-a]quinoxaline derivatives, original and structural analogues of alkaloid chimanine B and of previously described 4-alkenylpyrrolo[1,2-a]quinoxalines, was synthesized in good yields using efficient palladium-catalyzed Suzuki-Miyaura cross-coupling reactions. These new compounds were tested for in vitro antiparasitic activity upon three Leishmania spp. strains. Biological results showed activity against the promastigote forms of L. major, L. mexicana and L. donovani with IC50 ranging from 1.2 to 14.7 μM. In attempting to investigate if our pyrrolo[1,2-a]quinoxaline derivatives are broad-spectrum antiprotozoal compounds activities toward one Trypanosoma brucei brucei strain and the W2 and 3D7 Plasmodium falciparum strains were also investigated. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine J774 and human HepG2 cell lines. Structure-activity relationships of these new synthetic compounds are here discussed. © 2014 Elsevier Inc. All rights reserved.
Published: 2014
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28. Antileishmanial pharmacomodulation in 8-nitroquinolin-2(1H)-one series

Author: Michèle Laget, Lucie Paloque, Charline Kieffer, Sébastien Hutter, Caroline Castera-Ducros, Alexis Valentin, Pierre Verhaeghe, Nadine Azas, Patrice Vanelle, Pascal Rathelot, Anita Cohen, Sylvain Rault, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Normandie Université (NU), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Institut de Chimie Radicalaire ( ICR ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques ( IP-TPT ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Service de Santé des Armées-Université de Montpellier ( UM ), Laboratoire de chimie de coordination ( LCC ), Centre National de la Recherche Scientifique ( CNRS ), Université de Toulouse, UPS, Centre d'Etudes et de Recherche sur le Médicament de Normandie ( CERMN ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Normandie Université ( NU ), Pharmacochimie et Pharmacologie Pour le Développement ( PHARMA-DEV ), and Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique ( CNRS )
Subjects: Stereochemistry, Phosphorylcholine, Clinical Biochemistry, Leishmania donovani, Antiprotozoal Agents, Pharmaceutical Science, 01 natural sciences, Biochemistry, [ CHIM ] Chemical Sciences, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Parasitic Sensitivity Tests, Drug Discovery, parasitic diseases, medicine, Moiety, Humans, [CHIM]Chemical Sciences, Leishmania infantum, Cytotoxicity, Amastigote, Molecular Biology, Pentamidine, 030304 developmental biology, 0303 health sciences, Miltefosine, Life Cycle Stages, biology, 010405 organic chemistry, Chemistry, Macrophages, Organic Chemistry, Quinoline, Nitroquinolines, Hep G2 Cells, biology.organism_classification, In vitro, 3. Good health, 0104 chemical sciences, Drug Design, Molecular Medicine, medicine.drug
Abstract: International audience; An antileishmanial pharmacomodulation at position 4 of 8-nitroquinolin-2(1H)-one was conducted by using the Sonogashira and Suzuki-Miyaura coupling reactions. A series of 25 derivatives was tested in vitro on the promastigote stage of Leishmania donovani along with an in vitro cytotoxicity evaluation on the human HepG2 cell line. Only the derivatives bearing a phenyl moiety at position 4 of the quinoline ring displayed interesting biologic profile, when the phenyl moiety was substituted at the para position by a Br or Cl atom, or by a CF3 group. Among them, molecules 17 and 19 were the most selective and were then tested in vitro on the intracellular amastigote stage of both L. donovani and Leishmania infantum, in parallel with complementary in vitro cytotoxicity assays on the macrophage cell lines THP-1 and J774A.1. Molecule 19 showed no activity on the amastigote stages of the parasites and some cytotoxicity on the J774A.1 cell line while molecule 17, less cytotoxic than 19, showed anti-amastigote activity in L. infantum, being 3 times less active than miltefosine but more active and selective than pentamidine. Nevertheless, hit-molecule 17 did not appear as selective as the parent compound. (C) 2015 Elsevier Ltd. All rights reserved.
Published: 2015
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29. Discovery of new thienopyrimidinone derivatives displaying antimalarial properties toward both erythrocytic and hepatic stages of Plasmodium

Author: Audrey Lorthiois, Sylvain Rault, Anita Cohen, Pascal Rathelot, Carol Hopkins Sibley, Lucie Paloque, Maxime D. Crozet, Aurélien Lesnard, Pierre Verhaeghe, Peggy Suzanne, Eric Deharo, Nadine Azas, Patrice Vanelle, Louise Basmaciyan, Jean-Charles Lancelot, Patrick Dallemagne, Sébastien Hutter, Aurélien Dumètre, Michèle Laget, Dominique Mazier, Alexis Valentin, Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), WorldWide Antimalarial Resistance Network (WWARN), Université de Washington Seattle, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Normandie Université (NU), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Activity against Plasmodium liver stages, Erythrocytes, In vitro antiplasmodial profile, Parasitemia, Pharmacology, 01 natural sciences, Mice, Chloroquine, Cricetinae, Drug Discovery, Antiplasmodial mechanism of action, 0303 health sciences, biology, Chemistry, antiplasmodial profile, Hep G2 Cells, General Medicine, 3. Good health, Liver, Biochemistry, Thieno[3,2-dlpyrimidin-4(3H)-one, Plasmodium yoelii, medicine.drug, Plasmodium falciparum, CHO Cells, Antimalarials, Structure-Activity Relationship, 03 medical and health sciences, Cricetulus, In vitro, In vivo, parasitic diseases, medicine, Animals, Humans, [CHIM]Chemical Sciences, Trophozoites, IC50, Cell Proliferation, 030304 developmental biology, 2-d]pyrimidin-4(3H)-one, 010405 organic chemistry, Organic Chemistry, biology.organism_classification, medicine.disease, Malaria, 0104 chemical sciences, Pyrimidines, Specific activity, Pharmacomodulation, Thieno[3, Genotoxicity
Abstract: International audience; A preliminary in vitro screening of compounds belonging to various chemical families from our library revealed the thieno[3,2-d]pyrimidin-4(3H)-one scaffold displayed a promising profile against Plasmodium falciparum. Then, 120 new derivatives were synthesized and evaluated in vitro; compared to drug references, 40 showed good activity toward chloroquine sensitive (IC50 35-344 nM) and resistant (IC50 45-800 nM) P. falciparum strains. They were neither cytotoxic (CC50 15-50 mu M) toward HepG2 and CHO cells, nor mutagenic. Structure activity relationships were defined. The lead-compound also appeared active against the Plasmodium liver stages (Plasmodium yoelii IC50 = 35 nM) and a preliminary in vivo evaluation indicated the in vitro activity was preserved (45% reduction in parasitemia compared to untreated infected mice). A mechanistic study demonstrated these molecules do not involve any of the pathways described for commercial drugs and exert a specific activity on the ring and trophozoite stages. 2015 Elsevier Masson SAS. All rights reserved.
Published: 2015
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30. Looking for new antileishmanial derivatives in 8-nitroquinolin-2(1H)-one series

Author: Patrice Vanelle, Sylvain Rault, Charline Kieffer, Pascal Rathelot, Anita Cohen, Caroline Castera-Ducros, Nadine Azas, Pierre Verhaeghe, Sébastien Hutter, Manel Kraiem M'Rabet, Michèle Laget, Vincent Remusat, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Normandie Université (NU), Institut de Chimie Radicalaire ( ICR ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques ( IP-TPT ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Service de Santé des Armées-Université de Montpellier ( UM ), Laboratoire de chimie de coordination ( LCC ), Centre National de la Recherche Scientifique ( CNRS ), Centre d'Etudes et de Recherche sur le Médicament de Normandie ( CERMN ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Normandie Université ( NU ), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Stereochemistry, Substituent, Antiprotozoal Agents, Ring (chemistry), 01 natural sciences, [ CHIM ] Chemical Sciences, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Parasitic Sensitivity Tests, Drug Discovery, Molecule, [CHIM]Chemical Sciences, Solubility, Cytotoxicity, Pharmacology, 0303 health sciences, Trifluoromethyl, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, 030306 microbiology, Organic Chemistry, Nitroquinolines, General Medicine, 0104 chemical sciences, chemistry, Pharmacophore, Methyl group, Leishmania donovani
Abstract: International audience; From a recently identified antileishmanial pharmacophore, a structure activity relationship study was conducted by introducing various aminated, phenoxy or thiophenoxy moieties at position 4 of the 8-nitroquinolin-2(1H)-one scaffold, using SNAr reactions. Thus a series of 47 derivatives was synthesized and evaluated in vitro on the promastigote stage of Leishmania donovani. In parallel, the cytotoxicity of the active molecules was tested on the human HepG2 cell line. The results we obtained showed that the introduction of a substituent at position 4 of the antileishmanial pharmacophore can either lead to inactive or active derivatives, depending on the nature of the substituent. Aminated moieties appear as very unfavorable toward antileishmanial activity, while phenoxy or thiophenoxy moieties were shown to maintain the in vitro antileishmanial profile, especially when the phenyl ring of these moieties was substituted at the para or ortho position by a halogen atom (except fluorine), a trifluoromethyl group or a methyl group. Most of these derivatives showed a lack of solubility in the culture media which hindered the in vitro determination of both their cytotoxicity and activity against the intracellular amastigoste stage of L. donovani. (C) 2014 Elsevier Masson SAS. All rights reserved.
Published: 2015
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31. New series of monoamidoxime derivatives displaying versatile antiparasitic activity

Author: Ahlem Bouhlel, Patrice Vanelle, Nicolas Primas, Vincent Remusat, Sébastien Hutter, Thierry Terme, Anita Cohen, Christophe Curti, Clémence Tabélé, Nadine Azas, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), AMU, CNRS, and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées
Subjects: Spectrometry, Mass, Electrospray Ionization, Stereochemistry, Antiparasitic, medicine.drug_class, Manganese(III) acetate, Leishmania donovani, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Coupling reaction, Inhibitory Concentration 50, chemistry.chemical_compound, Oximes, Drug Discovery, parasitic diseases, Dihydrofuran, medicine, Phenyl group, Antiprotozoan activity in vitro, Carbon-13 Magnetic Resonance Spectroscopy, Cytotoxicity in vitro, Pharmacology, Antiparasitic Agents, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, General Medicine, biology.organism_classification, Amidoximes, chemistry, Wittig reaction, Pharmacomodulation, Palladium-catalyzed coupling reactions, Pharmacophore
Abstract: International audience; Following the promising antileishmanial results previously obtained in monoamidoxime series, a new series of derivatives was synthesized using manganese(III) acetate, Wittig reactions and Suzuki-Miyaura cross coupling reactions. Pharmacomodulation in R1, R2 or R3 substituents on the amidoxime structure is shown to influence antiprotozoan activity in vitro: a monosubstituted phenyl group in R1 (32-35) led to an activity against Leishmania donovani promastigotes (32, IC50 = 9.16 μM), whereas a polysubstituted group (36-37) led to an activity against Plasmodium falciparum (36, IC50 = 2.76 μM). Modulating chemical substituents in R2 and R3 only influenced the antiplasmodial activity in vitro. This suggests that the amidoxime scaffold has properties that could make it a promising new antiparasitic pharmacophore.
Published: 2014
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32. Targeting the human parasite Leishmania donovani: discovery of a new promising anti-infectious pharmacophore in 3-nitroimidazo[1,2-a]pyridine series

Author: Maxime D. Crozet, Lucie Paloque, Sébastien Hutter, Nadine Azas, Anita Cohen, Vincent Remusat, Caroline Castera-Ducros, Magali Casanova, Pascal Rathelot, Michèle Laget, Floriane Tanguy, Christophe Cantelli, Pierre Verhaeghe, Patrice Vanelle, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie, biologie et radicaux libres - UMR 6517 (CBRL), Université de la Méditerranée - Aix-Marseille 2-Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT-FR 2599), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Université Fédérale Toulouse Midi-Pyrénées, Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Stereochemistry, Cell Survival, Pyridines, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Leishmania donovani, Antiprotozoal Agents, Drug Evaluation, Preclinical, Pharmaceutical Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Biochemistry, Chemical library, Cell Line, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Drug Discovery, medicine, Potency, [CHIM]Chemical Sciences, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Molecular Biology, IC50, ComputingMilieux_MISCELLANEOUS, Miltefosine, biology, 010405 organic chemistry, Organic Chemistry, Imidazoles, Hep G2 Cells, biology.organism_classification, In vitro, 0104 chemical sciences, 3. Good health, chemistry, Molecular Medicine, Pharmacophore, medicine.drug, Pentamidine
Abstract: We report herein the discovery of antileishmanial molecules based on the imidazo[1,2-a]pyridine ring. In vitro screenings of imidazopyridines belonging to our chemical library, toward the promastigotes stage of Leishmania donovani, J774A.1 murine and HepG2 human cells, permitted to identify three selective hit-compounds (12, 20 and 28). New derivatives were then synthesized to allow structure-activity and -toxicity relationships analyses, enabling to characterize a lead-compound (44) displaying both a high potency (IC50=1.8 μM) and a good selectivity index, in comparison with three antileishmanial reference drug-compounds (amphotericin B, miltefosine and pentamidine). Moreover, lead-compound 44 also exhibits good in vitro activity against the intracellular amastigote stage of L. donovani. Thus, the 6-halo-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridine scaffold appears as a new promising selective antileishmanial pharmacophore, especially when substituted at position 8 by a bromine atom.
Published: 2013
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33. A decade of Plasmodium falciparum metabolic pathways of therapeutic interest to develop new selective antimalarial drugs

Author: Nadine Azas, Anita Cohen, and Aurélien Dumètre
Subjects: Pharmacology, biology, Plasmodium falciparum, General Medicine, Computational biology, biology.organism_classification, Genome, Metabolic pathway, Antimalarials, parasitic diseases, Drug Discovery, Animals
Abstract: Plasmodium falciparum has a specific metabolism of particular interest because several of its features, with respect to the host human ones, are potential pharmacological targets. Such features have been more intensely investigated since 2002, thanks to the full sequencing of the genome of P. falciparum. In this review, we are interested in the potential metabolic targets of therapeutic interest identified and investigated over the past decade in terms of lead-to-drug development.
Published: 2013

34. ChemInform Abstract: Tandem Synthesis and in vitro Antiplasmodial Evaluation of New Naphtho[2,1-d]thiazole Derivatives

Author: Maxime D. Crozet, Nadine Azas, Pierre Verhaeghe, Sébastien Hutter, Patrice Vanelle, Anita Cohen, and Pascal Rathelot
Subjects: chemistry.chemical_compound, Tandem, Chemistry, Stereochemistry, General Medicine, Thiazole, In vitro
Abstract: Derivatives (IIIb) and (Vb) exhibit an encouraging in vitro antiplasmodial activity on the K1 multi-resistant P.
Published: 2013
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35. Internet resources for anthropology

Author: Julia A. Hendon and Anita Cohen-Williams
Subjects: Internet resources, Media studies, Sociology, Library and Information Sciences, Education
Published: 1995
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36. Synthesis and Promising in Vitro Antiproliferative Activity of Sulfones of a 5-Nitrothiazole Series

Author: Vanelle, Anita Cohen, Maxime Crozet, Pascal Rathelot, Nadine Azas, and Patrice
Subjects: 5-nitrothiazole, sulfones, microwave irradiation, in vitro antiproliferative, HepG2 cell line, activity cellular specificity
Abstract: The synthesis in water of new sulfone derivatives under microwave irradiation is described. This eco-friendly process leads to the expected products in good yields by reaction of various substituted sulfinates (commercially available or obtained by reduction of the corresponding sulfonyl chlorides) with 4-chloromethyl-2-methyl-5-nitro-1,3-thiazole. In order to evaluate the antiproliferative effect of these compounds, several sulfone derivatives are also dichlorinated on the Cα next to the sulfonyl group. An evaluation on different cancer cell lines reveals promising selective in vitro antiproliferative activity toward HepG2 human cell lines by dihydrogenated sulfones, suggesting further research should be to explore their anticancer potential in the treatment of liver cancer.
Published: 2012
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37. Tandem synthesis and in vitro antiplasmodial evaluation of new naphtho[2,1-d] thiazole derivatives

Author: Maxime D. Crozet, Anita Cohen, Sébastien Hutter, Patrice Vanelle, Pascal Rathelot, Pierre Verhaeghe, Nadine Azas, Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Chimie, biologie et radicaux libres - UMR 6517 (CBRL), Université de la Méditerranée - Aix-Marseille 2-Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Stereochemistry, Plasmodium falciparum, Antiprotozoal Agents, Chemistry Techniques, Synthetic, 010402 general chemistry, 01 natural sciences, chemistry.chemical_compound, Biological profile, Drug Discovery, Humans, Moiety, [CHIM]Chemical Sciences, Thiazole, Pharmacology, Tandem, 010405 organic chemistry, Organic Chemistry, Hep G2 Cells, General Medicine, Combinatorial chemistry, In vitro, 0104 chemical sciences, Thiazoles, chemistry, Intramolecular force, Microwave irradiation, Knoevenagel condensation
Abstract: International audience; A series of naphtho[2,1-d]thiazoles was prepared in good yields under microwave irradiation with an original protocol combining tandem direct arylation and intramolecular Knoevenagel reaction on 1,3-thiazole derivatives. Antiplasmodial evaluation of this series highlighted two hit compounds (compounds 11 and 13) displaying promising in vitro activity on the multiresistant K1 Plasmodium falciparum strain. Structure-toxicity and structure activity relationships are also discussed and reveal the importance of the R-1 and R-4 substituents of the naphthyl moiety for the biological profile of the series. (C) 2012 Elsevier Masson SAS. All rights reserved.
Published: 2012
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38. A New Synthetic Route to Original Sulfonamide Derivatives in 2-Trichloromethylquinazoline Series: A Structure-Activity Relationship Study of Antiplasmodial Activity

Author: Nicolas, Primas, Pierre, Verhaeghe, Anita, Cohen, Charline, Kieffer, Aurélien, Dumètre, Sébastien, Hutter, Sylvain, Rault, Pascal, Rathelot, Nadine, Azas, Patrice, Vanelle, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Centre d'Etudes et de Recherche sur le Médicament de Normandie ( CERMN ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées
Subjects: Sulfonamides, Magnetic Resonance Spectroscopy, Cell Death, Plasmodium falciparum, Hep G2 Cells, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, antiplasmodial activity, Article, microwaves, lcsh:QD241-441, Antimalarials, Inhibitory Concentration 50, Structure-Activity Relationship, lcsh:Organic chemistry, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, sulfonamide, trichloromethyl group, Quinazolines, Humans, ComputingMilieux_MISCELLANEOUS, quinazoline
Abstract: International audience; We report herein a simple and efficient two-step synthetic approach to new 2-trichloromethylquinazolines possessing a variously substituted sulfonamide group at position 4 used to prepare new quinazolines with antiparasitic properties. Thus, an original series of 20 derivatives was synthesized, which proved to be less-toxic than previously synthesized hits on the human HepG2 cell line, but did not display significant antiplasmodial activity. A brief Structure-Activity Relationship (SAR) evaluation shows that a more restricted conformational freedom is probably necessary for providing antiplasmodial activity.
Published: 2012
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39. Reviews

Author: Paul A. Shackel, Vergil E. Noble, Charles E. Cleland, Jack S. Williams, David B. Landon, Steven D. Smith, Larry McKee, Craig A. Hanson, Anita Cohen-Williams, Margot Winer, Lawrence E. Babits, and James T. Rock
Subjects: Archeology, History, Anthropology, Gender studies, Sociology, Meaning (existential)
Published: 1993
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40. An efficient aqueous microwave-assisted Suzuki–Miyaura cross-coupling reaction in the thiazole series

Author: Anita Cohen, Maxime D. Crozet, Patrice Vanelle, and Pascal Rathelot
Subjects: Aqueous solution, Aqueous medium, Chemistry, Photochemistry, Pollution, High yielding, Microwave assisted, Combinatorial chemistry, Coupling reaction, chemistry.chemical_compound, Tetrabutylammonium bromide, Microwave irradiation, Environmental Chemistry, Thiazole
Abstract: A new simple, rapid and high yielding synthesis of various 5-substituted thiazoles by Suzuki–Miyaura cross-coupling reaction is described using microwave irradiation in aqueous medium without organic co-solvent in the presence of tetrabutylammonium bromide.
Published: 2009
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41. A woman like you: Women scientists and engineers at Brookhaven National Laboratory

Author: Barbara Franz, Susan Eng, Anita Cohen, Carmen Benkovitz, Harriet Martin, Louise Hanson, Iris Mastrangelo, Katherine Vivirito, Nicole Bernholc, Geraldine Lamble, Patricia Gorden, Maria-Alicia Villela, Victoria McLane, Rosario Enriquez-Leder, and Avril D. Woodhead
Subjects: Engineering, Work (electrical), business.industry, Technician, Science and engineering, Workforce, Engineering ethics, Applied research, Women in science, National laboratory, business
Abstract: This publication by the women in Science and Engineering introduces career possibilities in science and engineering. It introduces what work and home life are like for women who have already entered these fields. Women at Brookhaven National Laboratory work in a variety of challenging research roles -- from biologist and environmental scientist to safety engineer, from patent lawyer to technician. Brookhaven National Laboratory is a multi-program laboratory which carries out basic and applied research in the physical, biomedical and environmental sciences and in selected energy technologies. The Laboratory is managed by Associated University, Inc., under contract with the US Department of Energy. Brookhaven and the other national laboratories, because of their enormous research resources, can play a critical role in a education and training of the workforce.
Published: 1991
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42. Prise en charge des urgences vétérinaires chez le chien et le chat à l'officine

Author: Hairabian-Dossetto, Jade, Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), and Anita Cohen
Subjects: Conseil à l'officine, Urgences vétérinaires, Chat, [SDV]Life Sciences [q-bio], Urgences, Chien, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Pharmacie vétérinaire, Pharmacie d'officine
Abstract: Les animaux de compagnie, de plus en plus nombreux, occupent une place primordiale dans les foyers français. Le pharmacien d’officine, expert du médicament, est le professionnel de santé le plus accessible et est donc très souvent sollicité pour des conseils vétérinaires. Grâce à ses connaissances, le pharmacien est un acteur essentiel dans la prévention, les soins quotidiens et les soins d’urgence pour ces animaux. Ce travail se concentre sur les conseils adaptés aux chiens et aux chats qui sont les animaux de compagnie les plus présents en France.Au comptoir, le rôle du pharmacien est de répondre aux demandes de conseils des propriétaires mais également d’analyser une ordonnance vétérinaire et de dispenser des médicaments vétérinaires ou des médicaments à usage humain dans le cadre de la cascade vétérinaire. Son rôle est également de mener des actions de prévention et ainsi d’éviter la survenue des situations d’urgence. Les médicaments vétérinaires sont intégrés au monopole pharmaceutique et leur délivrance (ainsi que celle des autres produits vétérinaires) doit se faire dans le respect des règles de dispensation comme cela est fait lors d’une délivrance de médicaments pour l’homme, suivant une règlementation stricte et avec les conseils associés afin d’assurer la sécurité d’emploi de ces médicaments. Le pharmacien intervient en complément du vétérinaire, il est disponible rapidement pour orienter les propriétaires, notamment en cas d’urgence. Dans le but d’optimiser la prise en charge des urgences vétérinaires chez le chien et le chat, ce travail synthétise les éléments qui doivent retenir l’attention du pharmacien, les points importants à relever en cas d’urgence tels que la saison, la région, la présence de plaie…, et les gestes à réaliser, sous forme de fiches pratiques qui seront rassemblées dans un carnet afin de créer un outil d’aide au comptoir. La pharmacie vétérinaire représente une part croissante de l’activité de l’officine et fait partie intégrante des missions du pharmacien d’officine.
Published: 2022

43. Conseil vétérinaire en officine : définition et prise en charge thérapeutique des parasites externes et internes chez le chien

Author: Selles, Anaïs, Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), and Anita Cohen
Subjects: Conseil officinal, [SDV]Life Sciences [q-bio], Parasites internes, Médicaments antiparasitaires vétérinaires, Chien, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Pharmacie vétérinaire, Parasites externes
Abstract: En France, 63 millions d’animaux de compagnie sont recensés, de sorte qu’un foyer sur deux en possède au moins un. Ces chiffres font de la France, le pays de l’Union Européenne présentant la plus grande densité d’animaux de compagnie. De plus, la loi n°2015-177 du 16 février 2015, modifiant le statut juridique des animaux reconnus comme « des êtres vivants doués de sensibilité », a renforcé la position de l’animal dans les foyers.Dans ce contexte, l’attente des propriétaires d’animaux domestiques vis-à-vis des professionnels de santé a considérablement évolué, le pharmacien d’officine étant ainsi de plus en plus sollicité pour ses conseils en matière de prévention. Cependant, une analyse locale de terrain auprès d’un échantillon d’officines a permis de mettre en évidence une tendance générale dans ce cadre : faible connaissance des spécialités vétérinaires disponibles au comptoir et défaut avéré de conseil.L’objectif de ce travail de thèse est ainsi d’apporter une information simple et pratique aux pharmaciens d’officine, dans le but de les aider à structurer leurs discours et conseils en matière de pharmacie vétérinaire, afin que vétérinaires et pharmaciens puissent collaborer efficacement dans les soins apportés aux animaux.Dans le cadre de cette thèse, nous proposons un recueil des principaux parasites externes et internes connus chez le chien avec analyse des pathologies et traitements préventifs et curatifs recommandés, ainsi que des fiches conseils à l’attention des équipes officinales.Ainsi, chacune des deux parties seront développées selon un plan défini : présentation du parasite avec analyse de son cycle de développement, de sa période d’exposition maximale, analyse de son pouvoir pathogène (symptomatologie, diagnostic, traitement) et de son risque vectoriel notamment sur l’homme.
Published: 2019

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