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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antitubercular Agents / chemical synthesis*
-
Antitubercular Agents / pharmacology*
-
Antitubercular Agents / toxicity
-
Chlorocebus aethiops
-
Drug Delivery Systems*
-
Drug Design
-
Humans
-
Mycobacterium bovis / drug effects
-
Mycobacterium bovis / growth & development
-
Mycobacterium tuberculosis / drug effects*
-
Mycobacterium tuberculosis / enzymology*
-
Mycobacterium tuberculosis / growth & development
-
Nucleoside-Phosphate Kinase / antagonists & inhibitors*
-
Nucleoside-Phosphate Kinase / metabolism
-
Pyrimidines / chemical synthesis*
-
Pyrimidines / pharmacology*
-
Pyrimidines / toxicity
-
Vero Cells
Substances
-
Antitubercular Agents
-
Pyrimidines
-
Nucleoside-Phosphate Kinase
-
dTMP kinase