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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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-00167037
Contributor : Hélène Munier-Lehmann <>
Submitted on : Thursday, August 16, 2007 - 2:20:57 PM
Last modification on : Monday, January 13, 2020 - 5:08:10 PM

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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, Wiley-VCH Verlag, 2003, 15, pp.2911-2918. ⟨10.1002/ejoc.200300177⟩. ⟨pasteur-00167037⟩

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