He Xin, Alian Akram, Stroud Robert, Ortiz de Montellano Paul R
Department of Pharmaceutical Chemistry, University of California, 600 16 Street, San Francisco, California 94158-2517, USA.
J Med Chem. 2006 Oct 19;49(21):6308-23. doi: 10.1021/jm060715y.
In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antituberculosis agent with novel structures. InhA, the enoyl acyl carrier protein reductase (ENR) from M. tuberculosis, is one of the key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective antimicrobial target. We report here the discovery, through high-throughput screening, of a series of pyrrolidine carboxamides as a novel class of potent InhA inhibitors. Crystal structures of InhA complexed with three inhibitors have been used to elucidate the inhibitor binding mode. The potency of the lead compound was improved over 160-fold by subsequent optimization through iterative microtiter library synthesis followed by in situ activity screening without purification. Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA.
鉴于结核分枝杆菌的多重耐药性在全球范围内传播，迫切需要发现具有新颖结构的抗结核药物。InhA是结核分枝杆菌的烯酰基载体蛋白还原酶（ENR），是参与分枝杆菌脂肪酸延长循环的关键酶之一，并且已被确认为有效的抗菌靶点。我们在此报告通过高通量筛选发现了一系列吡咯烷羧酰胺，它们是一类新型的强效InhA抑制剂。已利用与三种抑制剂复合的InhA的晶体结构来阐明抑制剂的结合模式。通过迭代微孔板文库合成随后进行无需纯化的原位活性筛选，经过后续优化，先导化合物的效力提高了160倍以上。几种抑制剂外消旋混合物的拆分表明，只有一种对映体作为InhA的抑制剂具有活性。
