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

Kiran S Toti, Frederick Verbeke, Martijn D P Risseeuw, Vladimir Frecer, Hélène Munier-Lehmann, Serge Van Calenbergh

Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences (FFW), Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.

Bioorganic & medicinal chemistry 2013 Jan 1

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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. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

Kiran S Toti, Frederick Verbeke, Martijn D P Risseeuw, Vladimir Frecer, Hélène Munier-Lehmann, Serge Van Calenbergh. Synthesis and evaluation of 5'-modified thymidines and 5-hydroxymethyl-2'-deoxyuridines as Mycobacterium tuberculosis thymidylate kinase inhibitors. Bioorganic & medicinal chemistry. 2013 Jan 1;21(1):257-68