Rational design of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters as growth inhibitors of Mycobacterium tuberculosis. A potent and selective series for further drug development

Annamaria Lilienkampf, Marco Pieroni, Baojie Wan, Yuehong Wang, Scott G. Franzblau, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

New antituberculosis (anti-TB) drugs are urgently needed to shorten the 6-12month treatment regimen and especially to battle drug-resistant Mycobacterium tuberculosis (Mtb) strains. In this study, we have continued our efforts to develop isoxazole-based anti-TB compounds by applying rational drug design approach. The biological activity and the structure-activity relationships (SAR) for a designed series of 5-phenyl-3-isoxazolecarboxylic acid ethyl ester derived anti-TB compounds were investigated. Several compounds were found to exhibit nanomolar activity against the replicating bacteria (R-TB) and low micromolar activity against the nonreplicating bacteria (NRP-TB). The series showed excellent selectivity toward Mtb, and in general, no cytotoxicity was observed in Vero cells (IC50>128 μM). Notably, selected compounds also retained their activity against isoniazid (INH), rifampin (RMP), and streptomycin (SM) resistant Mtb strains. Hence, benzyloxy, benzylamino, and phenoxy derivatives of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters represent a highly potent, selective, and versatile series of anti-TB compounds and as such present attractive lead compounds for further TB drug development.

Original languageEnglish (US)
Pages (from-to)678-688
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number2
DOIs
StatePublished - 2010
Externally publishedYes

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Growth Inhibitors
Mycobacterium tuberculosis
Esters
Pharmaceutical Preparations
Isoxazoles
Bacteria
Multidrug-Resistant Tuberculosis
Vero Cells
Drug Design
Isoniazid
Streptomycin
Structure-Activity Relationship
Rifampin
Inhibitory Concentration 50
5-phenyl-3-isoxazolecarboxylic acid

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Rational design of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters as growth inhibitors of Mycobacterium tuberculosis. A potent and selective series for further drug development. / Lilienkampf, Annamaria; Pieroni, Marco; Wan, Baojie; Wang, Yuehong; Franzblau, Scott G.; Kozikowski, Alan P.

In: Journal of Medicinal Chemistry, Vol. 53, No. 2, 2010, p. 678-688.

Research output: Contribution to journalArticle

Lilienkampf, Annamaria ; Pieroni, Marco ; Wan, Baojie ; Wang, Yuehong ; Franzblau, Scott G. ; Kozikowski, Alan P. / Rational design of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters as growth inhibitors of Mycobacterium tuberculosis. A potent and selective series for further drug development. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 2. pp. 678-688.
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