Quantitative structure-activity relationship studies on nitrofuranyl anti-tubercular agents

Kirk Hevener, David M. Ball, John K. Buolamwini, Richard E. Lee

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

A series of nitrofuranylamide and related aromatic compounds displaying potent activity against Mycobacterium tuberculosis have been investigated utilizing 3-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used to produce 3D-QSAR models that correlated the minimum inhibitory concentration (MIC) values against M. tuberculosis with the molecular structures of the active compounds. A training set of 95 active compounds was used to develop the models, which were then evaluated by a series of internal and external cross-validation techniques. A test set of 15 compounds was used for the external validation. Different alignment and ionization rules were investigated as well as the effect of global molecular descriptors including lipophilicity (c Log P, Log D), polar surface area (PSA), and steric bulk (CMR), on model predictivity. Models with greater than 70% predictive ability, as determined by external validation, and high internal validity (cross-validated r2 > .5) have been developed. Incorporation of lipophilicity descriptors into the models had negligible effects on model predictivity. The models developed will be used to predict the activity of proposed new structures and advance the development of next generation nitrofuranyl and related nitroaromatic anti-tuberculosis agents.

Original languageEnglish (US)
Pages (from-to)8042-8053
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number17
DOIs
StatePublished - Sep 1 2008

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Quantitative Structure-Activity Relationship
Mycobacterium tuberculosis
Microbial Sensitivity Tests
Molecular Structure
Tuberculosis
Aromatic compounds
Molecular structure
Ionization

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Quantitative structure-activity relationship studies on nitrofuranyl anti-tubercular agents. / Hevener, Kirk; Ball, David M.; Buolamwini, John K.; Lee, Richard E.

In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 17, 01.09.2008, p. 8042-8053.

Research output: Contribution to journalArticle

Hevener, Kirk ; Ball, David M. ; Buolamwini, John K. ; Lee, Richard E. / Quantitative structure-activity relationship studies on nitrofuranyl anti-tubercular agents. In: Bioorganic and Medicinal Chemistry. 2008 ; Vol. 16, No. 17. pp. 8042-8053.
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