Flavin-Dependent Thymidylate Synthase (FDTS) encoded by ThyX gene was discovered as a new class of thymidylate synthase involved in the de novo synthesis of dTMP named only in 30 % of human pathogenic bacteria. This target was pursed for the development of new antibacterial agents against multiresistant pathogens. We have developed a new class of ANPs based on the mimic of two natural’s cofactors (dUMP and FAD) as inhibitors against Mycobacterium tuberculosis ThyX. Several synthetic efforts were performed to optimize regioselective N1-alkylation, cross-coupling metathesis and Sonogashira cross-coupling. Compound 19c showed a poor 31.8% inhibitory effect on ThyX at 200 μM.

由 ThyX 基因编码的黄素依赖性胸苷酸合酶( FDTS ) 被发现是一类新的胸苷酸合酶，参与dTMP 的从头合成，仅在 30% 的人类致病菌中命名。该目标旨在开发针对多重耐药病原体的新型抗菌剂。我们开发了一类基于模拟两种天然辅因子（dUMP 和 FAD）的新型 ANP，作为抗结核分枝杆菌 ThyX 的抑制剂。进行了一些合成工作以优化区域选择性 N1-烷基化、交叉偶联复分解和 Sonogashira 交叉偶联。化合物19c在 200 μM 时对 ThyX 显示出 31.8% 的不良抑制作用。