Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity, Angew Chem Int Ed Engl, 57(13):3478-3482，19 Mar 2018

Angewandte Chemie International Edition, 57(13):3478-3482，19 ;Mar 2018，DOI: 10.1002/anie.201800260

Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity

Michael B. Harbut, Baiyuan Yang, Renhe Liu, Takahiro Yano, Catherine Vilchèze, Bo Cheng, Jonathan Lockner, Hui Guo, Chenguang Yu, Scott G Franzblau, H. Mike Petrassi, William R. Jacobs Jr., Harvey Rubin, Arnab K. Chatterjee, Feng Wang

Abstract

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？nm 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.

文章链接：https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201800260