Substituted benzyl-pyrimidines targeting thymidine monophosphate kinase of Mycobacterium tuberculosis: Synthesis and in vitro anti-mycobacterial activity

A series of N1-(4-substituted-benzyl)-pyrimidines were synthesized as potential inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). Key SAR parameters included the chain length substitution in para position of the benzyl ring, the functional group terminating the alkyl chain, and the substituent on the C-5 pyrimidine ring. Synthesized molecules were assayed against both recombinant enzyme and mycobacteria cultures. The most potent compounds have Ki values in the micromolar range and an MIC50 of 50 μg/mL against Mycobacterium bovis. These results will guide the design of a new generation of lead compounds.

A series of N1-(4-substituted-benzyl)-pyrimidines as potential inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis were synthesized and evaluated for their ability to inhibit recombinant enzyme and mycobacterial growth in vitro.Figure optionsDownload as PowerPoint slide