Synthesis and evaluation of 5'-modified thymidines and 5-hydroxymethyl-2'-deoxyuridines as Mycobacterium tuberculosis thymidylate kinase inhibitors.

Kiran S Toti (1) , Frederick Verbeke (1) , Martijn D P Risseeuw (1) , Vladimir Frecer (2) , Hélène Munier-Lehmann (3) , Serge van Calenbergh (4)

1 Laboratory for Medicinal Chemistry
2 Department of Physical Chemistry of Drugs
3 Chimie et Biocatalyse
4 Laboratory for Medicinal Chemistry-FWW

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.

Domains: Life Sciences [q-bio]

Kiran S Toti, Frederick Verbeke, Martijn D P Risseeuw, Vladimir Frecer, Hélène Munier-Lehmann, et al.. Synthesis and evaluation of 5'-modified thymidines and 5-hydroxymethyl-2'-deoxyuridines as Mycobacterium tuberculosis thymidylate kinase inhibitors.. Bioorganic and Medicinal Chemistry, 2013, 21 (1), pp.257-68. ⟨10.1016/j.bmc.2012.10.018⟩. ⟨pasteur-00849837⟩