Mycobacterium tuberculosis thymidine monophosphate kinase inhibitors: Biological evaluation and conformational analysis of 2 '- and 3 '-modified thymidine analogues - Institut Pasteur Access content directly
Journal Articles European Journal of Organic Chemistry Year : 2003

Mycobacterium tuberculosis thymidine monophosphate kinase inhibitors: Biological evaluation and conformational analysis of 2 '- and 3 '-modified thymidine analogues

Abstract

Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) has recently been introduced as a potential target for the structure-based design of anti-tuberculosis drugs. Based on the TMPKmt X-ray structure and previous S.A.R. studies, we synthesised the nucleoside analogues 3a-b, 6a-b, 7a-b, and 8a-b, modified in 2'- and T-position of the ribofuranose ring moiety. To our surprise, these analogues showed only moderate binding affinity (i.e. K-i between 118 and 1260 pm). This prompted us to investigate the conformational features of these nucleosides. We concluded that compounds of this series, especially 8a-b, are strongly biased towards the "Northern" furanose ring conformation, whereas X-ray crystallography reveals a preference of TMPKmt for the opposite "Southern" conformers. This paper covers the synthesis, biological evaluation and conformational features (i.e. preferred ring puckering) of the 2'- and T-modified dT analogues.

Dates and versions

pasteur-00167037 , version 1 (16-08-2007)

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Philippe van Rompaey, Koen Nauwelaerts, Veerle Vanheusden, Jef Rozenski, Hélène Munier-Lehmann, et al.. Mycobacterium tuberculosis thymidine monophosphate kinase inhibitors: Biological evaluation and conformational analysis of 2 '- and 3 '-modified thymidine analogues. European Journal of Organic Chemistry, 2003, 15, pp.2911-2918. ⟨10.1002/ejoc.200300177⟩. ⟨pasteur-00167037⟩

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