ANTIPROZOAL PHARMACOCHEMISTRY IN QUINAZOLINE AND QUINOLINE SERIES : SYNTHESIS, BIOLOGICAL EVALUATION AND RESEARCH FOR THE MECHANISM OF ACTION

Le paludisme et la leishmaniose sont les deux plus importantes infections parasitaires au monde, en termes de mortalité. La recherche de nouvelles molécules actives contre les protozoaires responsables de ces « maladies tropicales négligées », Plasmodium sp et Leishmania sp, est un enjeu majeur de santé publique. Après une première partie dressant un état des lieux des connaissances disponibles en matière de chimiothérapie antiplasmodiale, une seconde partie s’est intéressée à l’étude des propriétés anti-infectieuses du noyau 2-trichlorométhyl-quinazoline, en introduisant en position 4 des motifs alcynyles par couplage de Sonogashira, optimisés par LC/MS. Une troisième partie a porté sur la pharmacomodulation en positions 2 et 4 du même noyau, notamment par réactions de SNAr. Une quatrième partie a consisté à rechercher le mécanisme d'action des meilleures quinazolines antiplasmodiales, via une approche de chromatographie d'affinité sur inhibiteur immobilisé. La fonctionnalisation multi-étapes des molécules les plus puissantes, par un bras espaceur, a été suivie de leur ancrage sur divers supports solides, pour constituer des matrices biocompatibles spécifiques. L’une d’entre-elles a permis la mise en évidence de 2 cibles plasmodiales protéiques originales : la GTPase Pfrab6 et la pyruvate-kinase PfpyrK1. Enfin, une cinquième partie relate la pharmacomodulation antileishmanienne du noyau 8-nitroquinoléin-2(1H)-one. Les travaux se sont intéressés à l'étude de la substitution de la position 4 de ce noyau par des réactions de SNAr, ainsi que des réactions de couplages pallado-catalysés optimisées à l’aide de la technologie micro-ondes.Malaria and leishmaniasis are the two most important parasitic infections worldwide, in terms of mortality. Thus, the research for new molecules targeting the protozoa parasites responsible for these “neglected tropical diseases”, Plasmodium sp and Leishmania sp, constitute a major challenge in public health. Our work focused first on a current state of knowledge about antiplasmodial chemotherapy. In a view to develop the study of the anti-infective properties of the 2-trichloromethylquinazoline scaffold, a second part presented antiplasmodial pharmacomodulation at position 4 using Sonogashira cross-coupling reaction, optimized with the LC/MS technology. A third part concerned other pharmacomodulation reactions, especially at positions 2 and 4, using especially SNAR reactions. A fourth part consisted in the research of the mechanism of action of the best antiplasmodial quinazolines by using the affinity chromatography on immobilized inhibitor approach. The multi-step functionalization of the most potent derivatives by a spacer side chain was followed by their anchoring onto various solid supports, so as to generate different biocompatible specific matrices. One of them, put in contact with a parasitic lysate, allowed the identification of two original plasmodial targets: the GTPase Pfrab6 and the pyruvate-kinase PfpyrK1. Finally, a fifth part presented the antileishmanial pharmacomodulation of the 8-nitroquinolin-2(1H)-one scaffold, especially at position 4 of the quinoline ring, involving SNAr reactions (with amines, phenols or thiophenols) or pallado-catalyzed coupling reactions (in particular Suzuki-Miyaura), some of them being optimized under microwave irradiation

Azobenzene Photoswitches in Proteolysis Targeting Chimeras

Publisher Copyright: © 2022 The Authors. ChemistrySelect published by Wiley-VCH GmbH.The photoswitchable-PROTACs have photoswitches that work as an actual ON/OFF switch for any particular bioactivity. In reported studies, the ON/OFF activity correlates with the photostationary state and quantum yield of a specific isomer under a definite wavelength of light, providing a spatiotemporal control over protein degradation (an example of photochemistry-based precision medicine). The studies reported the role of azobenzenes as photoswitches (ortho-tetramethoxybenzenes, ortho-tetraflurobenzenes as push-pull and push-push) to develop light-controlled PROTACs. This paper discussed the photophysical properties of photoswitchable-PROTACs (such as photoisomerization, quantum yield, and thermal relaxation states) and correlated their photochemical-based structural bioactivity relationships. The proteins studied under photoswitchable-PROTACs are kinase proteins: BCR-ABL fusion protein, ABL; Bromodomain proteins: BRD2, 3, 4; Immunophilins: FKBP12.Peer reviewe

Noncellular screening for the discovery of protein–protein interaction modulators

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PROTAC technology: A new drug design for chemical biology with many challenges in drug discovery

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Computational Tool to Design Small Synthetic Inhibitors Selective for XIAP-BIR3 Domain

International audienceX-linked inhibitor of apoptosis protein (XIAP) exercises its biological function by locking up and inhibiting essential caspase-3,-7 and-9 toward apoptosis execution. It is overexpressed in multiple human cancers, and it plays an important role in cancer cells' death skipping. Inhibition of XIAP-BIR3 domain and caspase-9 interaction was raised as a promising strategy to restore apoptosis in malignancy treatment. However, XIAP-BIR3 antagonists also inhibit cIAP1-2 BIR3 domains, leading to serious side effects. In this study, we worked on a theoretical model that allowed us to design and optimize selective synthetic XIAP-BIR3 antagonists. Firstly, we assessed various MM-PBSA strategies to predict the XIAP-BIR3 binding affinities of synthetic ligands. Molecular dynamics simulations using hydrogen mass repartition as an additional parametrization with and without entropic term computed by the interaction entropy approach produced the best correlations. These simulations were then exploited to generate 3D pharmacophores. Following an optimization with a training dataset, five features were enough to model XIAP-BIR3 synthetic ligands binding to two hydrogen bond donors, one hydrogen bond acceptor and two hydrophobic groups. The correlation between pharmacophoric features and computed MM-PBSA free energy revealed nine residues as crucial for synthetic ligand binding

A new DMAP-catalyzed and microwave-assisted approach for introducing heteroarylamino substituents at position 4 of the quinazoline ring.

International audienceWe report herein a new methodology for synthesizing quinazoline derivatives bearing an heteroarylamino moiety at position 4 of the quinazoline ring. As an alternative to the Buchwald-Hartwig cross-coupling reaction which appears, until now, as the only efficient way to react 4-chloroquinazolines with numerous amino nitrogen-containing heterocycles displaying poor nucleophilicity, we developed a DMAP-catalyzed reaction involving microwave irradiation. Optimization of the reaction conditions led to the use of 30 mol% of DMAP in toluene, using a monomode microwave reactor and sealed vials. Moreover, the SNAr reaction intermediate salt was isolated and fully characterized. Finally, the procedure was extended to two different 2-substitued-quinazoline series and also to various anilines, demonstrating that this approach was a general efficient way to access to such 4-substituted quinazoline scaffolds of high pharmaceutical interest

Sonogashira cross-coupling reaction in 4-chloro-2-trichloromethylquinazoline series is possible despite a side dimerization reaction

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A New Synthetic Route to Original Sulfonamide Derivatives in 2-Trichloromethylquinazoline Series: A Structure-Activity Relationship Study of Antiplasmodial Activity

International audienceWe 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

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

International audienceFrom 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 asandless cytotoxic than their quinazoline counterparts. Such pharmacomodulation in quinoxaline series not only provided a new antiplasmodial reference hit-molecule (IC50 = 0.4 μM, selectivity index = 100), but also highlighted an active (IC50 = 0.4 μM) and quite selective (SI = 265) synthesis intermediate

Sequential one pot double C H heteroarylation of thiophene using bromopyridines to synthesize unsymmetrical 2,5-bipyridylthiophenes

International audienceWe present Csingle bondH heteroarylation reactions between thiophene and variously substituted bromopyridines. The objective was to synthesize unsymmetrical 2,5-bipyridylthiophenes. We studied the reaction conditions allowing to a sequential one-pot double Csingle bondH heteroarylation, in a view to introduce two different pyridyl moieties at positions 2 and 5 of the thiophene ring using bromopyridines. 11 original unsymmetrical 2,5-bipyridylthiophenes were synthesized and characterized, including 2,5-di(pyridin-2-yl)thiophenes for which the preparation by classical cross-coupling reactions is challenging. Finally, with the additional synthesis of both an unsymmetrical 2,5-biarylthiophene and an original pyrimidin-thiophene-furan scaffold, we shown that our methodology was also an efficient tool to access to new heterocyclic sequence