Synthesis of sulfamide analogues of deoxthymidine monophosphate as potential inhibitors of mycobacterial cell wall biosynthesis

Abstract

The recently discovered enzyme Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), which catalyses the phosphorylation of deoxythymidine monophosphate (dTMP) to give deoxythymidine diphosphate (dTDP), is indispensable for the growth and survival of M. tuberculosis as it plays an essential role in DNA synthesis. Inhibition of TMPKmt is an attractive avenue for the development of novel anti-tuberculosis agents. Based on the premise that sulfamide may be a suitable isostere of phosphate, deoxythymidine analogues comprising various substituted sulfamides at C5′ were modelled in silico into the active site of TMPKmt (PDB accession code: 1N5K) using induced-fit docking methods. A selection of modelled compounds was synthesized, and their activity as inhibitors of TMPKmt was evaluated. Three compounds showed competitive inhibition of TMPKmt in the micromolar range (10–50 μM). Compounds were tested in vitro for anti-mycobacterial activity against M. smegmatis: three compounds showed weak anti-mycobacterial activity (MIC 250 μg/mL).