title: 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.
abstract: New antituberculosis (anti-TB) drugs are urgently needed to shorten the 6-12 month 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 (IC(50) > 128 muM). 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.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, Illinois 60612, USA.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Lilienkampf
authors.forename: Marco
authors.initials: M
authors.lastname: Pieroni
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002522:Chlorocebus aethiops; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004952:Esters; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D004952:Esters; D007555:Isoxazoles; C029570:5-phenyl-3-isoxazolecarboxylic acid