Novel Antitubercular 6-Dialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: Structure–Activity Relationship and Target Identification Studies

作者：Colin R. Wilson, Richard K. Gessner, Atica Moosa, Ronnett Seldon, Digby F. Warner, Valerie Mizrahi, Candice Soares de Melo, Sandile B. Simelane, Aloysius T. Nchinda, Efrem Abay, Dale Taylor, Mathew Njoroge, Christel Brunschwig, Nina Lawrence, Helena I. Boshoff, Clifton E. Barry, Frederick A. Sirgel, Paul D. van Helden, C.J. Harris, Richard K. Gordon, Sonja Ghidelli‐Disse, Hannah Pflaumer, Markus Böesche, Gerard Drewes, Olalla Sanz, Gracia Santos, María José Rebollo-López, Beatriz Urones, Carolyn Selenski, María José Lafuente-Monasterio, Matthew Axtman, Joël Lelièvre, Lluís Ballell, Rudolf Mueller, Leslie J. Street, Sandeep R. Ghorpade, Kelly Chibale · 发表于：Journal of Medicinal Chemistry · 年份：2017 · DOI：10.1021/acs.jmedchem.7b01347 · 被引用次数：24 · 研究领域：Tuberculosis Research and Epidemiology、Cancer therapeutics and mechanisms、Biochemical and Molecular Research

High Resolution Image Download MS PowerPoint Slide A BioFocus DPI SoftFocus library of ∼35 000 compounds was screened against Mycobacterium tuberculosis (Mtb) in order to identify novel hits with antitubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc 1 complex, disruption of cell–wall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization. Compounds from this series were active against clinical Mtb strains, while no cross-resistance to conventional antituberculosis drugs was observed. This suggested a novel mechanism of action, which was confirmed by chemoproteomic analysis leading to the identification of BCG_3193 and BCG_3827 as putative targets of the series with unknown function. Initial structure–activity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochemical properties.