7 results on '"Castera-Ducros Caroline"'
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2. 6-Chloro-3-nitro-8-(phenylthio)-2-[(phenylthio)methyl] imidazo[1,2- a ]pyridine.
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Paoli-Lombardo, Romain, Primas, Nicolas, Hutter, Sébastien, Bourgeade-Delmas, Sandra, Boudot, Clotilde, Castera-Ducros, Caroline, Jacquet, Inès, Courtioux, Bertrand, Azas, Nadine, Rathelot, Pascal, and Vanelle, Patrice
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PYRIDINE ,STRUCTURE-activity relationships ,CELL survival ,CELL lines ,PROMASTIGOTE - Abstract
As part of our ongoing antikinetoplastid structure–activity relationship study focused on positions 2 and 8 of the 3-nitroimidazo[1,2-a]pyridine scaffold, we were able to introduce a phenylthioether moiety at both position 2 and position 8 in one step. Using a previously reported synthetic route developed in our laboratory, we obtained 6-chloro-3-nitro-8-(phenylthio)-2-[(phenylthio)methyl]imidazo[1,2-a]pyridine in 74% yield. The in vitro cell viability of this compound was assessed on the HepG2 cell line, and its in vitro activity was evaluated against the promastigote form of L. donovani, the axenic amastigote form of L. infantum and the trypomastigote blood stream form of T. b. brucei. It showed low solubility in HepG2 culture medium (CC
50 > 7.8 µM), associated with weak activity against both the promastigote form of L. donovani (EC50 = 8.8 µM), the axenic amastigote form of L. infantum (EC50 = 9.7 µM) and the trypomastigote blood stream form of T. b. brucei (EC50 = 12.8 µM). [ABSTRACT FROM AUTHOR]- Published
- 2023
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3. 6-Chloro-3-nitro-2-[(phenylsulfonyl)methyl]imidazo[1,2- b ]pyridazine.
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Paoli-Lombardo, Romain, Primas, Nicolas, Hutter, Sébastien, Bourgeade-Delmas, Sandra, Boudot, Clotilde, Castera-Ducros, Caroline, Jacquet, Inès, Courtioux, Bertrand, Azas, Nadine, Rathelot, Pascal, and Vanelle, Patrice
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AMASTIGOTES ,PYRIDAZINES ,LEISHMANIA donovani ,LEISHMANIA infantum ,CELL survival ,CELL lines - Abstract
As part of our ongoing scaffold-hopping work on an antikinetoplastid 3-nitroimidazo[1,2-a]pyridine scaffold, we explored 3-nitroimidazo[1,2-b]pyridazine as a potential new antikinetoplastid series. Using conditions previously described by our lab, we obtained 6-chloro-3-nitro-2-[(phenylsulfonyl)methyl]imidazo[1,2-b]pyridazine with 54% yield. In vitro activity of this compound was evaluated against both the promastigote form of Leishmania donovani, the axenic amastigote form of Leishmania infantum and the trypomastigote blood stream form of Trypanosomabrucei brucei, and its influence on cell viability was assessed on the HepG2 cell line. However, despite good activity against the trypomastigote blood stream form of T. b. brucei (EC
50 = 0.38 µM), it showed poor solubility in both HepG2 (CC50 > 7.8 µM) and L. infantum axenic amastigotes (EC50 > 1.6 µM) culture media, associated with a loss of activity against the promastigote form of L. infantum (EC50 > 15.6 µM). [ABSTRACT FROM AUTHOR]- Published
- 2023
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4. Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2- a ]pyridine Antileishmanial Pharmacophore.
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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
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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 (CC
50 > 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
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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
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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, Damian, Destere, Alexandre, Wyllie, Susan, Fairlamb, Alan, Corvaisier, Sophie, Since, Marc, Malzert-Fréon, Aurélie, Di Giorgio, Carole, Rathelot, Pascal, Azas, Nadine, Courtioux, Bertrand, Vanelle, Patrice, Verhaeghe, Pierre, 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), Biologie Intégrative Santé Chimie Environnement (BISCEm), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), 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), 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), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Universidad de Navarra [Pamplona] (UNAV), CHU Limoges, University of Dundee, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Aix-Marseille Université, Université de Toulouse, and CNRS
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SARs ,Imidazo[1 2-a]pyridine ,Nitroaromatic ,Redox potentials ,Kinetoplastids ,[CHIM.COOR]Chemical Sciences/Coordination chemistry ,Nitroreductases - Abstract
International audience; To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = −0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.
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- 2020
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6. Nongenotoxic 3-Nitroimidazo[1,2- a ]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity
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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)
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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
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7. 8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi.
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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, and Since, Marc
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MOIETIES (Chemistry) , *SONOGASHIRA reaction , *TRYPANOSOMA cruzi , *HYDROXYL group , *REDUCTION potential - Abstract
An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2- a pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro , highlighting 3 potent (40 nM ≤ EC 50 blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti- T. brucei brucei molecules (19 , 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC 50 amastigotes = 1.2 μM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (−0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound. Image 1 • 20 original derivatives were synthesized in 3-nitroimidazopyridine series. • Introducing an alkynyl group at position 8 of the 3-nitroimidazopyridine scaffold improves antitrypanosomal activity. • 1 potent and selective hit-compound was identified against T. b. brucei & T. cruzi. • The hit compound showed good in vitro and in vivo PK parameters. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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