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Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity
Author(s) -
Harbut Michael B.,
Yang Baiyuan,
Liu Renhe,
Yano Takahiro,
Vilchèze Catherine,
Cheng Bo,
Lockner Jonathan,
Guo Hui,
Yu Chenguang,
Franzblau Scott G,
Petrassi H. Mike,
Jacobs William R.,
Rubin Harvey,
Chatterjee Arnab K.,
Wang Feng
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201800260
Subject(s) - antimycobacterial , mycobacterium tuberculosis , small molecule , chemistry , biochemistry , enzyme , drug discovery , dehydrogenase , combinatorial chemistry , tuberculosis , medicine , pathology
The generation of ATP through oxidative phosphorylation is an essential metabolic function for Mycobaterium tuberculosis ( Mtb ), regardless of the growth environment. The type II NADH dehydrogenase (Ndh‐2) is the conduit for electrons into the pathway, and is absent in the mammalian genome, thus making it a potential drug target. Herein, we report the identification of two types of small molecules as selective inhibitors for Ndh‐2 through a multicomponent high‐throughput screen. Both compounds block ATP synthesis, lead to effects consistent with loss of NADH turnover, and importantly, exert bactericidal activity against Mtb . Extensive medicinal chemistry optimization afforded the best analogue with an MIC of 90 n m against Mtb . Moreover, the two scaffolds have differential inhibitory activities against the two homologous Ndh‐2 enzymes in Mtb , which will allow precise control over Ndh‐2 function in Mtb to facilitate the assessment of this anti‐TB drug target.