5-苯基-3-异恶唑羧酸乙酯的合理设计作为结核分枝杆菌的生长抑制剂。这一系列化合物具有强大的选择性，可进一步开发成为药物。

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.

机构信息

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.

出版信息

J Med Chem. 2010 Jan 28;53(2):678-88. doi: 10.1021/jm901273n.

DOI:10.1021/jm901273n

PMID:20000577

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.

摘要

新的抗结核（抗-TB）药物迫切需要缩短 6-12 个月的治疗方案，特别是要对抗耐药结核分枝杆菌（Mtb）菌株。在这项研究中，我们继续努力开发基于异恶唑的抗结核化合物，采用合理的药物设计方法。设计了一系列 5-苯基-3-异恶唑羧酸乙酯衍生的抗结核化合物，研究了它们的生物活性和构效关系（SAR）。发现几种化合物对复制细菌（R-TB）具有纳摩尔级的活性，对非复制细菌（NRP-TB）具有低微摩尔级的活性。该系列对结核分枝杆菌表现出极好的选择性，一般来说，在 Vero 细胞中没有观察到细胞毒性（IC 50 > 128 μM）。值得注意的是，所选化合物对异烟肼（INH）、利福平（RMP）和链霉素（SM）耐药结核分枝杆菌菌株也保持活性。因此，5-苯基-3-异恶唑羧酸乙酯的苄氧基、苄氨基和苯氧基衍生物代表了一类高效、选择性和多功能的抗结核化合物，是进一步开发结核病药物的有吸引力的先导化合物。