Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98109, United States.
J Med Chem. 2023 Nov 9;66(21):14724-14734. doi: 10.1021/acs.jmedchem.3c01273. Epub 2023 Oct 23.
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 (), and an anilinoquinazoline (AQA) that also had potent activity against nonreplicating and persistent . 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 infection. The structure-activity relationship of this dually active compound identified the pyridyl-6-methyl group as being required for potent inhibition but a liability for P450 metabolism. Pyrrolopyrimidine () emerged as the optimal compound that balanced micromolar inhibition of nonreplicating and TGFBR1 while also demonstrating improved metabolic stability and pharmacokinetic profiles.
结核病（TB）控制因耐药性的出现而变得复杂。有希望的预防耐药性的策略是针对非复制、耐药细菌群体和宿主，但针对这两者的抑制剂和靶点仍然很少。在基于细胞的 ATP 竞争性抑制剂筛选中，我们发现了具有针对复制性（）的体外活性的化合物，以及一种对非复制性和持久性（）也具有强大活性的苯胺喹唑啉（AQA）。AQA 最初是为了抑制人类转化生长因子受体 1（TGFBR1）而开发的，TGFBR1 是一种宿主激酶，预计在结核分枝杆菌感染期间会对宿主产生不利影响。这种双重活性化合物的构效关系确定了吡啶-6-甲基基团是强效（）抑制所必需的，但对细胞色素 P450 代谢不利。吡咯并嘧啶（）作为最佳化合物脱颖而出，它平衡了对非复制性和 TGFBR1 的微摩尔抑制，同时还表现出改善的代谢稳定性和药代动力学特征。
