Rational design of new antituberculosis agents: receptor-independent four-dimensional quantitative structure-activity relationship analysis of a set of isoniazid derivatives

J Med Chem. 2004 Jul 15;47(15):3755-64. doi: 10.1021/jm049913k.

Abstract

A 4D-QSAR analysis was carried out for a set of 37 hydrazides whose minimum inhibitory concentrations against M. tuberculosis var. bovis were evaluated. These ligands are thought to act like isoniazid in mycolic acid biosynthesis. Results indicate that nonpolar groups in the acyl moiety of ligands markedly decrease biological activity. Molecular modifications of the ligand NAD moiety, including nonpolar groups and hydrogen bond donor and acceptor groups, seemingly improve ligand interactions with amino acid residues of the InhA active site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology
  • Binding Sites
  • Isoniazid / analogs & derivatives*
  • Isoniazid / chemistry*
  • Isoniazid / pharmacology
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Mycobacterium tuberculosis / drug effects
  • Quantitative Structure-Activity Relationship*

Substances

  • Antitubercular Agents
  • Isoniazid