Synthesis and structure–activity relationship studies of pyrido [1,2-e]purine-2,4(1H,3H)-dione derivatives targeting Flavin-Dependent $Thymidylate\ Synthase$ in $Mycobacterium\ tuberculosis$ - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Molecules Année : 2022

Synthesis and structure–activity relationship studies of pyrido [1,2-e]purine-2,4(1H,3H)-dione derivatives targeting Flavin-Dependent $Thymidylate\ Synthase$ in $Mycobacterium\ tuberculosis$

Résumé

In 2002, a new class of thymidylate synthase (TS) involved in the de novo synthesis of dTMP named Flavin-Dependent Thymidylate Synthase (FDTS) encoded by the thyX gene was discovered; FDTS is present only in 30% of prokaryote pathogens and not in human pathogens, which makes it an attractive target for the development of new antibacterial agents, especially against multi-resistant pathogens. We report herein the synthesis and structure-activity relationship of a novel series of hitherto unknown pyrido[1,2-E]purine-2,4(1H,3H)-dione analogues. Several synthetics efforts were done to optimize regioselective N1-alkylation through organopalladium cross-coupling. Modelling of potential hits were performed to generate a model of interaction into the active pocket of FDTS to understand and guide further synthetic modification. All those compounds were evaluated on an in-house in vitro NADPH oxidase assays screening as well as against Mycobacterium tuberculosis ThyX. The highest inhibition was obtained for compound 23a with 84.3% at 200 μM without significant cytotoxicity (CC50 > 100 micromolar) on PBM cells.
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hal-03798565 , version 1 (05-10-2022)

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Nicolas G. Biteau, Vincent Roy, Cyril Nicolas, Hubert F Becker, Jean-Christophe Lambry, et al.. Synthesis and structure–activity relationship studies of pyrido [1,2-e]purine-2,4(1H,3H)-dione derivatives targeting Flavin-Dependent $Thymidylate\ Synthase$ in $Mycobacterium\ tuberculosis$. Molecules, 2022, 27, pp.6216. ⟨10.3390/molecules27196216⟩. ⟨hal-03798565⟩
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