Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, 541199, China.
State Key Laboratory of Respiratory Disease, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China; Guangzhou National Laboratory, Guangzhou, 510005, China.
Eur J Med Chem. 2024 Dec 5;279:116806. doi: 10.1016/j.ejmech.2024.116806. Epub 2024 Aug 31.
In this study, a series of novel thieno [3, 2-b]pyridinone derivatives were designed and synthesized using a scaffold hopping strategy. Six compounds showed potent anti-mycobacterial activity (minimum inhibitory concentration (MIC) ≤ 1 μg/mL) against Mycobacterium tuberculosis (Mtb) UAlRa. Compound 6c displayed good activity against Mtb UAlRv (MIC = 0.5-1 μg/mL). Compounds 6c and 6i also showed activity against Mtb UAlRa in macrophages and exhibited low cytotoxicity against LO-2 cells. The selected compounds displayed a narrow antibacterial spectrum, with no activity against representative Gram-positive, Gram-negative bacteria, as well as fungi. Furthermore, compound 6c demonstrated favorable oral pharmacokinetic properties with a T value of 47.99 h and exhibited good in vivo activity in an acute mouse model of tuberculosis (TB). The target of compound 6c was identified as a NADH-dependent enoyl-acyl carrier protein reductase (InhA) by genome sequencing of spontaneously compound 6c-resistant Mtb mutants, indicating that compound 6c may not require activation and can directly target InhA. In vitro antimicrobial assays against a recombinant M. smegmatis overexpressing the Mtb-InhA, along with InhA inhibition assays, confirmed that InhA is the target of thieno [3, 2-b]pyridinone derivatives. Overall, this study identified thieno [3, 2-b]pyridinone scaffold as a novel chemotype that is promising for the development of anti-TB agents.
在这项研究中，我们采用了一种基于骨架跃迁的策略，设计并合成了一系列新型噻吩并[3,2-b]吡啶酮衍生物。其中，有 6 种化合物表现出了较强的抗分枝杆菌活性（最低抑菌浓度（MIC）≤1μg/mL），对结核分枝杆菌（Mtb）UAlRa 有较强的抑制作用。化合物 6c 对 Mtb UAlRv 的活性较好（MIC=0.5-1μg/mL）。化合物 6c 和 6i 对巨噬细胞中的 Mtb UAlRa 也具有活性，并且对 LO-2 细胞的细胞毒性较低。所选化合物的抗菌谱较窄，对代表性的革兰氏阳性菌、革兰氏阴性菌和真菌均无活性。此外，化合物 6c 具有良好的口服药代动力学特性，T 值为 47.99 h，并在急性结核小鼠模型中表现出良好的体内活性。通过对自发产生耐药性的 Mtb 突变株进行基因组测序，确定了化合物 6c 的靶标为 NADH 依赖性烯酰基辅酶 A 还原酶（InhA），这表明化合物 6c 可能不需要激活，可直接作用于 InhA。体外抗重组 M. smegmatis 实验和 InhA 抑制实验表明，噻吩并[3,2-b]吡啶酮衍生物的靶标为 Mtb-InhA。总体而言，本研究发现噻吩并[3,2-b]吡啶酮骨架是一种很有前途的抗结核药物化学结构。
