Synthesis and Evaluation of 5-Substituted 2′-deoxyuridine Monophosphate Analogues As Inhibitors of Flavin-Dependent Thymidylate Synthase in Mycobacterium tuberculosis

A series of 5-substituted 2′-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC50 value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC50 > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.