Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration

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• 作者：Renier van der Westhuyzen ; Susan Winks ; Colin R. Wilson ; Grant A. Boyle ; Richard K. Gessner ; Candice Soares de Melo ; Dale Taylor ; Carmen de Kock ; Mathew Njoroge ; Christel Brunschwig ; Nina Lawrence ; Srinivasa P.S. Rao ; Frederick Sirgel ; Paul van Helden ; Ronnett Seldon ; Atica Moosa ; Digby F. Warner ; Luca Arista ; Ujjini H. Manjunatha ; Paul W. Smith ; Leslie J. Street ; Kelly Chibale
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：December 10, 2015
• 年：2015
• 卷：58
• 期：23
• 页码：9371-9381
• 全文大小：496K
• ISSN：1520-4804

文摘

High-throughput screening of a library of small polar molecules against Mycobacterium tuberculosis led to the identification of a phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing the ester moiety with a methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents was designed and executed to explore structure鈥揳ctivity relationships with respect to the N-benzyl substituent, leading to compounds with nanomolar activity. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (螖cydKO) was hyper-susceptible to compounds from this series, and a strain carrying a single point mutation in qcrB, the gene encoding a subunit of the menaquinol cytochrome c oxidoreductase, was resistant to compounds in this series. In combination, these observations indicate that this novel class of antimycobacterial compounds inhibits the cytochrome bc1 complex, a validated drug target in M. tuberculosis.