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Start Over Author "Gellis, Armand" Topic structure-activity relationships
2 results on '"Gellis, Armand"'

1. Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-trichloromethyl Quinazolines

Author

Amrane, Dyhia, Gellis, Armand, Hutter, Sebastien, Prieri, Marion, Verhaeghe, Pierre, Azas, Nadine, Vanelle, Patrice, Primas, Nicolas, 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 [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), ANR-17-CE11-0017,NINTARMAL,Nouveaux inhibiteurs de Pfrab6 et PfpyrK1 ciblant le paludisme(2017), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), 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), and 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)

Subjects
Plasmodium falciparum, Structure-activity relationships, Hep G2 Cells, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Article, lcsh:QD241-441, Antimalarials, Structure-Activity Relationship, structure-activity relationships, lcsh:Organic chemistry, in vitro HepG2 cytotoxicity, Quinazolines, Humans, 2-trichloromethylquinazoline
Abstract

From three previously identified antiplasmodial hit compounds (A&ndash, C) and inactive series (D), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 P. falciparum strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC50 K1 P. falciparum &le, 2 &micro, M and SI &ge, 20) were identified among 4-carboxamido derivatives (2, 9, 16, and 24) and two among 4-alkoxy derivatives (41 and 44). Regarding the two most potent molecules (16 and 41), five derivatives without a 2-CCl3 group were prepared, evaluated, and appeared totally inactive (EC50 &gt, 50 &micro, M), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.

Published
2020
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2. Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold.

Author

Desroches, Justine, Kieffer, Charline, Primas, Nicolas, Hutter, Sébastien, Gellis, Armand, El-Kashef, Hussein, Rathelot, Pascal, Verhaeghe, Pierre, Azas, Nadine, and Vanelle, Patrice

Subjects
*STRUCTURE-activity relationship in pharmacology, *PLASMODIUM falciparum, *ANTIPROTOZOAL agents, *SUBSTITUENTS (Chemistry), *QUINAZOLINE, *THERAPEUTICS
Abstract

From 4 antiplasmodial hit-molecules identified in 2-trichloromethylquinazoline series, we conducted a global Structure-Activity relationship (SAR) study involving 26 compounds and covering 5 molecular regions (I – V), aiming at defining the corresponding pharmacophore and identifying new bioactive derivatives. Thus, after studying the aniline moiety in detail, thienopyrimidine, quinoline and quinoxaline bio-isosters were synthesized and tested on the K1 multi-resistant P. falciparum strain, along with a cytotoxicity evaluation on the human HepG2 cell line, to define selectivity indecies. SARs first showed that thienopyrimidines and quinolines were globally more cytotoxic, while quinoxaline analogs appeared as active as- and less cytotoxic than their quinazoline counterparts. Such pharmacomodulation in quinoxaline series not only provided a new antiplasmodial reference hit-molecule (IC 50 = 0.4 μM, selectivity index = 100), but also highlighted an active (IC 50 = 0.4 μM) and quite selective (SI = 265) synthesis intermediate. [ABSTRACT FROM AUTHOR]

Published
2017
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