Dual Inhibition of Mycobacterium tuberculosis and the Host TGFBR1 by an Anilinoquinazoline.
Dual Inhibition of Mycobacterium tuberculosis and the Host TGFBR1 by an Anilinoquinazoline.
复制标题
Anilinoquinazoline 对结核分枝杆菌和宿主 TGFBR1 的双重抑制。
DOI：
10.1021/acs.jmedchem.3c01273
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发表时间：
2023
影响因子：
7.3
通讯作者：
Grundner,Christoph
中科院分区：
文献类型：
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作者：
Nandakumar,Meganathan;Ollodart,Anja;Fleck,Neil;Kapadia,NiravR;Frando,Andrew;Boradia,Vishant;Smith,JefferyL;Chen,Junxi;Zuercher,WilliamJ;Willson,TimothyM;Grundner,Christoph
结核病的控制因耐药性的出现而复杂化。预防耐药的有希望的策略是靶向非复制、耐药细菌群体和靶向宿主，但这两种策略的抑制剂和靶标仍然很少。在基于细胞的atp竞争抑制剂筛选中，我们发现了具有体外抗复制结核分枝杆菌（Mtb）活性的化合物，以及苯胺喹唑啉（AQA），它也具有抗非复制和持续性结核分枝杆菌的有效活性。AQA最初被开发用于抑制人转化生长因子受体1 (TGFBR1)， TGFBR1是一种宿主激酶，预计在感染期间会对宿主产生不良影响。这种双活性化合物的构效关系表明，吡啶基-6-甲基是有效抑制甲基的必需物质，但对P450代谢有不利影响。吡咯嘧啶（43）是平衡微摩尔抑制非复制mtband TGFBR1的最佳化合物，同时也显示出改善的代谢稳定性和药代动力学特征。
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 replicatingMycobacterium tuberculosis(Mtb), and an anilinoquinazoline (AQA) that also had potent activity against nonreplicating and persistentMtb. AQA was originally developed to inhibit human transforming growth factor receptor 1 (TGFBR1), a host kinase that is predicted to have host-adverse effects duringMtbinfection. The structure–activity relationship of this dually active compound identified the pyridyl-6-methyl group as being required for potentMtbinhibition but a liability for P450 metabolism. Pyrrolopyrimidine (43) emerged as the optimal compound that balanced micromolar inhibition of nonreplicatingMtband TGFBR1 while also demonstrating improved metabolic stability and pharmacokinetic profiles.