Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI)
Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI)
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DOI：
10.1021/jm020050
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发表时间：
2002-07-18
影响因子：
7.3
通讯作者：
Huffman, WF
中科院分区：
文献类型：
--
作者：
Miller, WH;Seefeld, MA;Huffman, WF
细菌烯酰-ACP还原酶（FabI）催化细菌脂肪酸生物合成的每个循环的最后一步，并且是开发新的抗菌剂的有吸引力的靶标。我们的努力，以确定有效的，选择性的FabI抑制剂开始筛选葛兰素史克专有的化合物收集，确定了几个小分子抑制剂的金黄色葡萄球菌FabI。通过反复药物化学和基于X射线晶体结构的设计的组合，这些先导物之一被开发成新型氨基吡啶衍生物9，一种来自S.金黄色葡萄球菌（IC 50 = 2.4 μ M）和流感嗜血杆菌（IC 50 = 4.2 μ M）。化合物9对几种生物体具有良好的体外抗菌活性，包括S.金黄色葡萄球菌（MIC = 0.5 μ g/mL），并且在体内对S.金黄色葡萄球菌感染大鼠腹股沟脓肿模型。通过FabI过表达和大分子合成研究，9的作用模式已被证实是通过抑制FabI来抑制脂肪酸生物合成。总之，这些结果支持FabI作为有效的抗菌靶标，并证明了小分子FabI抑制剂治疗细菌感染的潜力。
Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the Glaxo-SmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC50 = 2.4 muM) and Haemophilus influenzae (IC50 = 4.2 muM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 mug/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.