靶向结核分枝杆菌1-脱氧-D-木酮糖5-磷酸合酶的化合物的构效关系
Structure-activity relationships of compounds targeting mycobacterium tuberculosis 1-deoxy-D-xylulose 5-phosphate synthase.
作者信息
Mao Jialin, Eoh Hyungjin, He Rong, Wang Yuehong, Wan Baojie, Franzblau Scott G, Crick Dean C, Kozikowski Alan P
机构信息
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
出版信息
Bioorg Med Chem Lett. 2008 Oct 1;18(19):5320-3. doi: 10.1016/j.bmcl.2008.08.034. Epub 2008 Aug 14.
Abstract
We report on a target-based approach to identify possible Mycobacterium tuberculosis DXS inhibitors from the structure of a known transketolase inhibitor. A small focused library of analogs was assembled in order to begin elucidating some meaningful structure-activity relationships of 3-(4-chloro-phenyl)-5-benzyl-4H-pyrazolo[1,5-a]pyrimidin-7-one. Ultimately we found that 2-methyl-3-(4-fluorophenyl)-5-(4-methoxy-phenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one, although still weak, was able to inhibit M. tuberculosis DXS with an IC(50) of 10.6 microM.
摘要
我们报告了一种基于靶点的方法，该方法从一种已知转酮醇酶抑制剂的结构出发来鉴定可能的结核分枝杆菌1-脱氧-D-木酮糖-5-磷酸合酶（DXS）抑制剂。为了开始阐明3-(4-氯苯基)-5-苄基-4H-吡唑并[1,5-a]嘧啶-7-酮的一些有意义的构效关系，我们构建了一个小型的类似物聚焦文库。最终我们发现，2-甲基-3-(4-氟苯基)-5-(4-甲氧基苯基)-4H-吡唑并[1,5-a]嘧啶-7-酮尽管活性仍然较弱，但能够以10.6微摩尔的半数抑制浓度（IC50）抑制结核分枝杆菌DXS。
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