Synthesis and evaluation of 5-substituted 2′-deoxyuridine monophosphate analogues as inhibitors of flavin-dependent thymidylate synthase in mycobacterium tuberculosis

摘要

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 IC_(50) value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC_(50) > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.