Search

Your search keyword '"Castera-Ducros Caroline"' showing total 41 results
Start Over Author "Castera-Ducros Caroline"
41 results on '"Castera-Ducros Caroline"'

1. Structural simplification of the 3‐nitroimidazo[1,2‐a]pyridine antileishmanial pharmacophore: Design, synthesis, and antileishmanial activity of novel 2,4-disubstituted 5-nitroimidazoles

Author

Paoli-Lombardo Romain, Primas Nicolas, Hutter Sébastien, Castera-Ducros Caroline, Jacquet Inès, Verhaeghe Pierre, Azas Nadine, Rathelot Pascal, and Vanelle Patrice

Subjects
structural simplification, 5-nitroimidazole, vicarious nucleophilic substitution (vns), tetrakis(dimethylamino)ethylene (tdae), antileishmanial activity, Organic chemistry, QD241-441
Abstract

As part of our ongoing antileishmanial structure–activity relationship study, a structural simplification of the 3‐nitroimidazo[1,2‐a]pyridine ring to a 5-nitroimidazole moiety was conducted. A series of novel 2,4-disubsituted 5-nitroimidazole derivatives, including the 5-nitroimidazole analog of Hit A and the 4-phenylsulfonylmethyl analog of fexinidazole, were obtained by using the vicarious nucleophilic substitution of hydrogen (VNS) reaction, to substitute position 4, and by using the tetrakis(dimethylamino)ethylene methodology to modulate position 2. The molecular structures of eight novel 5-nitroimidazoles were characterized by 1H NMR, 13C NMR, LC/MS, and HRMS. The in vitro antileishmanial activity of these compounds was evaluated against the promastigote form of Leishmania infantum and their influence on cell viability was assessed on the human hepatocyte HepG2 cell line. The 4-phenylsulfonylmethyl analog of fexinidazole showed the best selectivity index of the series, displaying good activity against both the promastigote form of L. infantum (EC50 = 0.8 µM, SI > 78.1) and the promastigote form of Leishmania donovani (EC50 = 4.6 µM, SI > 13.6), and exhibiting low cytotoxicity on the HepG2 cell line (CC50 > 62.5 µM).

Published
2024
Full Text
View/download PDF

3. 2,2 ′ -[2,4-Bis(4-chlorophenyl)cyclobutane-1,3-diyl]bis(8-bromo-6-chloro-3-nitroimidazo[1,2- a ]pyridine).

Author

Jacquet, Inès, Paoli-Lombardo, Romain, Castera-Ducros, Caroline, Vanelle, Patrice, and Primas, Nicolas

Subjects
X-ray crystallography, MOLECULAR structure, PYRIDINE derivatives, RING formation (Chemistry), PYRIDINE
Abstract

In the context of our ongoing studies on 3-nitroimidazo[1,2-a]pyridine derivatives as potent antileishmanial compounds, we isolated a new unexpected compound from the spontaneous cycloaddition of N-[2-(8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridin-2-yl)-1-(4-chlorophenyl)ethyl]-4-methylbenzenesulfonamide. The molecular structure was fully characterized by using 1H and 13C NMR, X-ray crystallography, and HRMS. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

5. Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

Author

Fersing, Cyril, Boudot, Clotilde, Paoli-Lombardo, Romain, Primas, Nicolas, Pinault, Emilie, Hutter, Sébastien, Castera-Ducros, Caroline, Kabri, Youssef, Pedron, Julien, Bourgeade-Delmas, Sandra, Sournia-Saquet, Alix, Stigliani, Jean-Luc, Valentin, Alexis, Azqueta, Amaya, Muruzabal, Damián, Destere, Alexandre, Wyllie, Susan, Fairlamb, Alan H., Corvaisier, Sophie, Since, Marc, Malzert-Fréon, Aurélie, Di Giorgio, Carole, Rathelot, Pascal, Azas, Nadine, Courtioux, Bertrand, Vanelle, Patrice, and Verhaeghe, Pierre

Published
2020
Full Text
View/download PDF

6. 8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi

Author

Fersing, Cyril, Boudot, Clotilde, Castera-Ducros, Caroline, Pinault, Emilie, Hutter, Sébastien, Paoli-Lombardo, Romain, Primas, Nicolas, Pedron, Julien, Seguy, Line, Bourgeade-Delmas, Sandra, Sournia-Saquet, Alix, Stigliani, Jean-Luc, Brossas, Jean-Yves, Paris, Luc, Valentin, Alexis, Wyllie, Susan, Fairlamb, Alan H., Boutet-Robinet, Élisa, Corvaisier, Sophie, Since, Marc, Malzert-Fréon, Aurélie, Destere, Alexandre, Mazier, Dominique, Rathelot, Pascal, Courtioux, Bertrand, Azas, Nadine, Verhaeghe, Pierre, and Vanelle, Patrice

Published
2020
Full Text
View/download PDF

7. 31st Annual GP2A Medicinal Chemistry Conference

Author

Primas, Nicolas, primary, Castera-Ducros, Caroline, additional, Paoli-Lombardo, Romain, additional, Curti, Christophe, additional, Mathias, Fanny, additional, Rathelot, Pascal, additional, Marchand, Pascal, additional, and Vanelle, Patrice, additional

Published
2024
Full Text
View/download PDF

8. Synthesis of Nitrostyrylthiazolidine-2,4-dione Derivatives Displaying Antileishmanial Potential.

Author

Khoumeri, Omar, Hutter, Sébastien, Primas, Nicolas, Castera-Ducros, Caroline, Carvalho, Sandra, Wyllie, Susan, Efrit, Mohamed Lotfi, Fayolle, Dimitri, Since, Marc, Vanelle, Patrice, Verhaeghe, Pierre, Azas, Nadine, and El-Kashef, Hussein

Subjects
VISCERAL leishmaniasis, DOSAGE forms of drugs, GROUP 15 elements, PHENYL group, LEISHMANIA infantum, ANTIPARASITIC agents
Abstract

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2–5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure–activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

9. Synthesis of new 5- or 7-substituted 3-nitroimidazo[1,2-a]pyridine derivatives using SNAr and palladium-catalyzed reactions to explore antiparasitic structure-activity relationships

Author

Paoli-Lombardo, Romain, additional, Primas, Nicolas, additional, Bourgeade-Delmas, Sandra, additional, Sournia-Saquet, Alix, additional, Castera-Ducros, Caroline, additional, Jacquet, Inès, additional, Verhaeghe, Pierre, additional, Rathelot, Pascal, additional, and Vanelle, Patrice, additional

Published
2023
Full Text
View/download PDF

10. 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

Author

Fersing, Cyril, Boudot, Clotilde, Pedron, Julien, Hutter, Sébastien, Primas, Nicolas, Castera-Ducros, Caroline, Bourgeade-Delmas, Sandra, Sournia-Saquet, Alix, Moreau, Alain, Cohen, Anita, Stigliani, Jean-Luc, Pratviel, Geneviève, Crozet, Maxime D., Wyllie, Susan, Fairlamb, Alan, Valentin, Alexis, Rathelot, Pascal, Azas, Nadine, Courtioux, Bertrand, Verhaeghe, Pierre, and Vanelle, Patrice

Published
2018
Full Text
View/download PDF

11. 31st Annual GP 2 A Medicinal Chemistry Conference.

Author

Primas, Nicolas, Castera-Ducros, Caroline, Paoli-Lombardo, Romain, Curti, Christophe, Mathias, Fanny, Rathelot, Pascal, Marchand, Pascal, and Vanelle, Patrice

Subjects
*PHARMACEUTICAL chemistry, *POSTER presentations, *CONFERENCES & conventions, *ORAL communication, *RESEARCH personnel
Abstract

The Group for the Promotion of Pharmaceutical Chemistry in Academia (GP2A) held its 31st annual conference in August 2023 at the Faculty of Pharmacy of Aix-Marseille University, Marseille, France. There were 8 keynote presentations, 10 early career researcher oral presentations and 23 poster presentations. Among them, four awards were delivered, two for best oral communications and two for the best poster presentations. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

13. 6-Chloro-3-nitro-8-(phenylthio)-2-[(phenylthio)methyl] imidazo[1,2-a]pyridine

Author

Paoli-Lombardo, Romain, primary, Primas, Nicolas, additional, Hutter, Sébastien, additional, Bourgeade-Delmas, Sandra, additional, Boudot, Clotilde, additional, Castera-Ducros, Caroline, additional, Jacquet, Inès, additional, Courtioux, Bertrand, additional, Azas, Nadine, additional, Rathelot, Pascal, additional, and Vanelle, Patrice, additional

Published
2023
Full Text
View/download PDF

15. 6-Chloro-3-nitro-2-[(phenylsulfonyl)methyl]imidazo[1,2-b]pyridazine

Author

Paoli-Lombardo, Romain, primary, Primas, Nicolas, additional, Hutter, Sébastien, additional, Bourgeade-Delmas, Sandra, additional, Boudot, Clotilde, additional, Castera-Ducros, Caroline, additional, Jacquet, Inès, additional, Courtioux, Bertrand, additional, Azas, Nadine, additional, Rathelot, Pascal, additional, and Vanelle, Patrice, additional

Published
2023
Full Text
View/download PDF

19. Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]pyridine Antileishmanial Pharmacophore

Author

Paoli-Lombardo, Romain, primary, Primas, Nicolas, additional, Bourgeade-Delmas, Sandra, additional, Hutter, Sébastien, additional, Sournia-Saquet, Alix, additional, Boudot, Clotilde, additional, Brenot, Emilie, additional, Castera-Ducros, Caroline, additional, Corvaisier, Sophie, additional, Since, Marc, additional, Malzert-Fréon, Aurélie, additional, Courtioux, Bertrand, additional, Valentin, Alexis, additional, Verhaeghe, Pierre, additional, Azas, Nadine, additional, Rathelot, Pascal, additional, and Vanelle, Patrice, additional

Published
2022
Full Text
View/download PDF

22. N -[1-(2-Chlorophenyl)-2-{1-methyl-5-nitro-4-[(phenylsulfonyl)methyl]-1 H -imidazol-2-yl}ethyl]-4-methylbenzenesulfonamide.

Author

Paoli-Lombardo, Romain, Primas, Nicolas, Castera-Ducros, Caroline, Jacquet, Inès, Rathelot, Pascal, and Vanelle, Patrice

Subjects
CARBANIONS, MOIETIES (Chemistry), HYDROGEN, ETHYLENE, SULFONES
Abstract

In continuation of our research program to develop original synthetic methods using TDAE methodology on nitroheterocyclic substrates, we were able to generate for the first time a stable carbanion in position 2 of the 5-nitroimidazole scaffold. Starting from a 2-chloromethyl-4-phenylsulfonylmethyl-5-nitroimidazole intermediate, prepared by the vicarious nucleophilic substitution of hydrogen (VNS) reaction, we selectively introduced a N-tosylbenzylimine moiety at position 2 without reducing the sulfone at position 4, leading to the formation of N-[1-(2-chlorophenyl)-2-{1-methyl-5-nitro-4-[(phenylsulfonyl)methyl]-1H-imidazol-2-yl}ethyl]-4-methylbenzenesulfonamide in 47% yield. This new synthetic method using TDAE should allow access to new 2-substituted 5-nitroimidazole derivatives with various electrophiles such as carbonyls and other N-tosylbenzylimines. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
View/download PDF

25. Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2- a ]pyridine Antileishmanial Pharmacophore.

Author

Paoli-Lombardo, Romain, Primas, Nicolas, Bourgeade-Delmas, Sandra, Hutter, Sébastien, Sournia-Saquet, Alix, Boudot, Clotilde, Brenot, Emilie, Castera-Ducros, Caroline, Corvaisier, Sophie, Since, Marc, Malzert-Fréon, Aurélie, Courtioux, Bertrand, Valentin, Alexis, Verhaeghe, Pierre, Azas, Nadine, Rathelot, Pascal, and Vanelle, Patrice

Subjects
SOLUBILITY, PYRIDINE, IMIDAZOPYRIDINES, STRUCTURE-activity relationships, PHARMACOKINETICS, LEISHMANIA donovani, DRUG solubility
Abstract

An antileishmanial structure–activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L. infantum and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-a]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC50 > 100 µM) associated with a good activity against the intracellular amastigote stage of L. infantum (EC50 = 3.7 µM versus 0.4 and 15.9 µM for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T1/2 > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

26. Nongenotoxic 3-Nitroimidazo[1,2- a ]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Author

Fersing, Cyril, Basmaciyan, Louise, Boudot, Clotilde, Pedron, Julien, Hutter, Sébastien, Cohen, Anita, Castera-Ducros, Caroline, Primas, Nicolas, Laget, Michèle, Casanova, Magali, Bourgeade-Delmas, Sandra, Piednoel, Meĺanie, Sournia-Saquet, Alix, Belle Mbou, Valère, Courtioux, Bertrand, Boutet-Robinet, Elisa, Since, Marc, Milne, Rachel, Wyllie, Susan, Fairlamb, Alan, Valentin, Alexis, Rathelot, Pascal, Verhaeghe, Pierre, Vanelle, Patrice, Azas, Nadine, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-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), 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-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)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), 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-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), CHU Limoges, Université de Limoges (UNILIM), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), University of Dundee, Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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), 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), Contaminants & Stress Cellulaire (ToxAlim-COMICS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), 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), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT), and Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN)

Subjects
nitroaromatic, Ames test, Ames, imidazopyridine, test, comet assay, nitroreductases, [SDV]Life Sciences [q-bio], parasitic diseases, Leishmania ssp, [CHIM.THER]Chemical Sciences/Medicinal Chemistry
Abstract

International audience; 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
Full Text
View/download PDF

27. New nitroaromatic candidats for trypanosomiasis therapeutics

Author

Boudot, Clotilde, Fersing, Cyril, Pedron, Julien, Mbou, Valere Belle, Castera-Ducros, Caroline, Primas, Nicolas, Cohen, Anita, Hutter, Sebastien, Bourgeade-Delmas, Sandra, Laget, Michèle, Boutet-Robinet, Elisa, Sournia-Saquet, Alix, Moreau, Alain, Azas, Nadine, Rathelot, Pascal, Vanelle, Patrice, Valentin, Alexis, Verhaeghe, Pierre, Courtioux, Bertrand, Neuroépidémiologie Tropicale (NET), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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-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)-Centre National de la Recherche Scientifique (CNRS)-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), 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 Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, 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), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), 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), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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), 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), Contaminants & Stress Cellulaire (ToxAlim-COMICS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), 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)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)

Subjects
nitroreductases, parasitic diseases, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, nitroaromatic drugs, African Trypanosomiasis
Abstract

International audience; African Trypanosomiasis is a neglected tropical disease, endemic in nearly 30 countries in sub-Saharan Africa. Trypanosoma brucei, the infectious agent responsible for the disease, is transmitted by the bite of Glossina (tsetse fly) and can affect both animals (AAT - Animal African Trypanosomiasis) and humans (HAT - Human African Trypanosomiasis). Without treatment, the disease is fatal. The current therapeutic care is complex and depends on trypanosome species, host and stage of the disease. Therefore, it is essential to find new treatments. In recent years, nitroaromatic compounds present a renewed interest as anti-infective agents like fexinidazole.Some studies show that their antiparasitic activity is based on their selective reduction by parasite nitroreductases (NTR). These NTR leading to metabolites that are cytotoxic for the protozoan.The objective of the study is to develop new nitroaromatic drugs efficient against Trypanosoma.Our collaboration between chemists and biologists allows to synthetize different molecules and test them on various biological models. Firstly, about 200 molecules belonging to the 8-nitroquinolin-2(1H)-one series and 3-nitroimidazo[1,2-a]pyridine series were synthetized. Secondly, in vitro evaluations were performed for all molecules on a HepG2 human cell line, and on a strain of T. b. brucei to evaluate the CC50 and IC50 respectively. In vitro pharmacokinetic tests and comet assays completed the data for the most promising molecules. The four best candidates were included in an in vivo test on a murine model of mice infected by T. b. brucei (strain AnTat 1.1E): briefly, the 4 molecules were tested to evaluate their ability to cross the blood brain barrier, their toxicity and their activity. At the end of the study, an anatomopathological analysis was performed to ensure the absence of damage on vital organs (brain, heart, kidney, liver). The finality of this project is to develop new drug candidates for human and animal therapeutic.

Published
2018

28. Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Author

Fersing, Cyril, primary, Basmaciyan, Louise, additional, Boudot, Clotilde, additional, Pedron, Julien, additional, Hutter, Sébastien, additional, Cohen, Anita, additional, Castera-Ducros, Caroline, additional, Primas, Nicolas, additional, Laget, Michèle, additional, Casanova, Magali, additional, Bourgeade-Delmas, Sandra, additional, Piednoel, Mélanie, additional, Sournia-Saquet, Alix, additional, Belle Mbou, Valère, additional, Courtioux, Bertrand, additional, Boutet-Robinet, Élisa, additional, Since, Marc, additional, Milne, Rachel, additional, Wyllie, Susan, additional, Fairlamb, Alan H., additional, Valentin, Alexis, additional, Rathelot, Pascal, additional, Verhaeghe, Pierre, additional, Vanelle, Patrice, additional, and Azas, Nadine, additional

Published
2018
Full Text
View/download PDF

30. Nongenotoxic 3‑Nitroimidazo[1,2‑a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity.

Author

Fersing, Cyril, Basmaciyan, Louise, Boudot, Clotilde, Pedron, Julien, Hutter, Sébastien, Cohen, Anita, Castera-Ducros, Caroline, Primas, Nicolas, Laget, Michèle, Casanova, Magali, Bourgeade-Delmas, Sandra, Piednoel, Mélanie, Sournia-Saquet, Alix, Belle Mbou, Valère, Courtioux, Bertrand, Boutet-Robinet, Élisa, Since, Marc, Milne, Rachel, Wyllie, Susan, and Fairlamb, Alan H.

Published
2019
Full Text
View/download PDF

32. Synthesis and Antiplasmodial Receptor Independent 4D-QSAR Study in 4-aryl-2-trichloromethylquinazoline Series

Author

Reboul, Jean-Pierre, primary, Verhaeghe, Pierre, additional, Siri, Didier, additional, Gaudel-Siri, Anouk, additional, Castera- Ducros, Caroline, additional, Dumètre, Aurélien, additional, Hutter, Sébastien, additional, Azas, Nadine, additional, Rathelot, Pascal, additional, Vanelle, Patrice, additional, and Iliadis, Athanassios, additional

Published
2013
Full Text
View/download PDF

40. Efficient Synthesis of New 8-Aryl Tricyclic Pyridinones.

Author

Castera-Ducros, Caroline, Crozet, Maxime D., and Vanelle, Patrice

Subjects
PYRIDONE synthesis, PYRIDINE, SUZUKI reaction, OLEFINATION reactions, MALONATES, RING formation (Chemistry), CARBOXYLATES
Abstract

New tricyclic pyridinones were synthesized from 6-bromo- 2-chloromethyl-3-nitroimidazo[1,2-a]pyridine in four steps involving a Suzuki-Miyaura cross-coupling reaction and a direct olefination with diethyl ketomalonate as key steps. Subsequent onepot reduction-cyclization provided new ethyl 8-aryl-2-oxo-1,2-dihydrodipyrido[ 1,2-a;3',2'-d]imidazole-3-carboxylates. [ABSTRACT FROM AUTHOR]

Published
2006
Full Text
View/download PDF

41. Nongenotoxic 3-Nitroimidazo[1,2- a ]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity.

Author

Fersing C, Basmaciyan L, Boudot C, Pedron J, Hutter S, Cohen A, Castera-Ducros C, Primas N, Laget M, Casanova M, Bourgeade-Delmas S, Piednoel M, Sournia-Saquet A, Belle Mbou V, Courtioux B, Boutet-Robinet É, Since M, Milne R, Wyllie S, Fairlamb AH, Valentin A, Rathelot P, Verhaeghe P, Vanelle P, and Azas N

Abstract

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., Competing Interests: The authors declare no competing financial interest.

Published
2018
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results