结核分枝杆菌
肺结核
化学
生长抑制
体外
抗药性
药理学
微生物学
生物
生物化学
医学
病理
作者
Meganathan Nandakumar,Anja R Ollodart,Neil Fleck,Nirav Kapadia,Andrew Frando,Vishant Mahendra Boradia,Jeffery L. Smith,Junxi Chen,William J. Zuercher,Timothy M. Willson,Christoph Grundner
标识
DOI:10.1021/acs.jmedchem.3c01273
摘要
Tuberculosis (TB) control is complicated by the emergence of drug resistance. Promising strategies to prevent drug resistance are the targeting of nonreplicating, drug-tolerant bacterial populations and targeting of the host, but inhibitors and targets for either are still rare. In a cell-based screen of ATP-competitive inhibitors, we identified compounds with in vitro activity against replicating Mycobacterium tuberculosis (Mtb), and an anilinoquinazoline (AQA) that also had potent activity against nonreplicating and persistent Mtb. AQA was originally developed to inhibit human transforming growth factor receptor 1 (TGFBR1), a host kinase that is predicted to have host-adverse effects during Mtb infection. The structure–activity relationship of this dually active compound identified the pyridyl-6-methyl group as being required for potent Mtb inhibition but a liability for P450 metabolism. Pyrrolopyrimidine (43) emerged as the optimal compound that balanced micromolar inhibition of nonreplicating Mtb and TGFBR1 while also demonstrating improved metabolic stability and pharmacokinetic profiles.
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