Synthesis and Biological Evaluation of Bicyclic Nucleosides as Inhibitors of M. tuberculosis Thymidylate Kinase

• Published in: ChemMedChem 2006-10, Vol.1 (10), p.1081-1090
• Main Authors: Van Daele, Ineke, Munier-Lehmann, Hélène, Hendrickx, Pieter M. S., Marchal, Gilles, Chavarot, Pierre, Froeyen, Matheus, Qing, Li, Martins, José C., Van Calenbergh, Serge
• Format: Article
• Language: English
• Subjects: Bicyclo Compounds, Heterocyclic; Binding Sites; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; conformational analysis; Crystallography, X-Ray; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Mycobacterium bovis; Mycobacterium bovis - drug effects; Mycobacterium tuberculosis; Mycobacterium tuberculosis - enzymology; Nucleoside-Phosphate Kinase; Nucleoside-Phosphate Kinase - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship; Thymidine; Thymidine - analogs & derivatives; Thymidine - chemical synthesis; Thymidine - pharmacology; thymidine analogues; TMPK inhibitors
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200600028

Herein we describe the synthesis and conformational analysis of a series of bicyclic thymidine derivatives and their evaluation as inhibitors of thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), based on previously discovered bicyclic sugar nucleosides. With a Ki value of 2.3 μm, 1‐[3‐aminomethyl‐3,5‐dideoxy‐2‐O,6‐N‐(thiocarbonyl)‐β‐D‐ribofuranosyl]thymine emerged as the most potent TMPK inhibitor of this series. Moreover, this promising compound displays inhibitory potency against Mycobacteria cultures with an IC99 value of 100 μg mL−1, thus promoting TMPKmt for the first time as a validated target for further inhibitory design. Attempts to rationalise the observed structure–activity relationship (SAR) involving molecular modelling and conformational analysis are described. Thymidine monophosphate kinase (TMPKmt) represents an attractive target for designing antituberculosis agents. The interesting structural features of bicyclic nucleoside 1, a previously discovered inhibitor of TMPKmt, led us to explore the SAR of a series of analogues of 1. The synthesis of these analogues is described, and biological data against TMPKmt and M. bovis are also presented.