Synthesis and evaluation of 5'-modified thymidines and 5-hydroxymethyl-2'-deoxyuridines as Mycobacterium tuberculosis thymidylate kinase inhibitors.
Toti KS, Verbeke F, Risseeuw MD, Frecer V, Munier-Lehmann H, Van Calenbergh S.
We report the synthesis of 5'-modified thymidines (16, 18, 21, 23) and 5,5'-bis-substituted 2'-deoxyuridine analogues (30, 47) as inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). These analogues were evaluated for their capacity to inhibit TMPKmt and solely two 5'-modified thymidines were found to possess moderate inhibitory activity. In addition, a feasibility study of protecting groups for the 5-CH(2)OH moiety of 2'-deoxyuridines is described that enables to introduce the desired 5'-modification.