Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 2, Pages 678-688Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm901273n
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Funding
- The Academy of Finland [120441]
- The Finnish Cultural Foundation
- Global Alliance for TB Drug Development
- Academy of Finland (AKA) [120441, 120441] Funding Source: Academy of Finland (AKA)
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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 (IC50 > 128 mu M). 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.
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