Synthesis and Structure–Activity Relationship Studies of Pyrido [1,2-<i>e</i>]Purine-2,4(<i>1H,3H</i>)-Dione Derivatives Targeting <i>Flavin-Dependent Thymidylate Synthase</i> in <i>Mycobacterium tuberculosis</i>

Abstract

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 μM) on PBM cells.

Keywords

• flavin-dependent thymidylate synthase
• pyrido[1,2-<i>e</i>]purine-2,4(1<i>H</i>,3<i>H</i>)-dione analogues
• structure-activity relationship
• sonogashira and Suzuki-Miyaura cross-coupling