title: Substituted benzyl-pyrimidines targeting thymidine monophosphate kinase of Mycobacterium tuberculosis: synthesis and in vitro anti-mycobacterial activity.
abstract: A series of N(1)-(4-substituted-benzyl)-pyrimidines were synthesized as potential inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). Key SAR parameters included the chain length substitution in para position of the benzyl ring, the functional group terminating the alkyl chain, and the substituent on the C-5 pyrimidine ring. Synthesized molecules were assayed against both recombinant enzyme and mycobacteria cultures. The most potent compounds have K(i) values in the micromolar range and an MIC(50) of 50microg/mL against Mycobacterium bovis. These results will guide the design of a new generation of lead compounds.
authors.affiliation: Unité de Chimie Organique, CNRS, URA2128, Département Biologie Structurale et Chimie, Institut Pasteur, 28, rue du Dr Roux, 75724 Paris cedex 15, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Gasse
authors.forename: Dominique
authors.initials: D
authors.lastname: Douguet
authors.forename: Valérie
authors.initials: V
authors.lastname: Huteau
authors.forename: Gilles
authors.initials: G
authors.lastname: Marchal
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pochet
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002522:Chlorocebus aethiops; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D009163:Mycobacterium bovis / Q000187:drug effects / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D011743:Pyrimidines; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase