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 T1/2 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.

中文翻译：

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通过靶向烯酰-ACP 还原酶在体内表现出对结核分枝杆菌有效活性的噻吩并[3,2-b]吡啶酮衍生物的设计与合成


在本研究中，使用支架跳跃策略设计并合成了一系列新型噻吩基 [3， 2-b] 吡啶酮衍生物。6 种化合物对结核分枝杆菌 （Mtb） UAlRa 显示出有效的抗分枝杆菌活性 （最低抑菌浓度 ≤ 1 μg/mL）。化合物 6c 对 Mtb UAlRv 表现出良好的活性 （MIC = 0.5–1 μg/mL）。化合物 6c 和 6i 在巨噬细胞中也显示出对 Mtb UAlRa 的活性，并且对 LO-2 细胞表现出低细胞毒性。所选化合物显示出较窄的抗菌谱，对代表性革兰氏阳性、革兰氏阴性细菌以及真菌没有活性。此外，化合物 6c 表现出良好的口服药代动力学特性，T1/2 值为 47.99 h，并且在急性结核病 （TB） 小鼠模型中表现出良好的体内活性。通过对自发化合物 6c 耐药的 Mtb 突变体进行基因组测序，将化合物 6c 的靶点鉴定为 NADH 依赖性烯酰酰基载体蛋白还原酶 （InhA），表明化合物 6c 可能不需要激活，可以直接靶向 InhA。针对过表达 Mtb-InhA 的重组耻垢分枝杆菌的体外抗菌测定以及 InhA 抑制测定证实，InhA 是噻吩并 [3， 2-b] 吡啶酮衍生物的靶标。总体而言，本研究确定噻吩并 [3， 2-b] 吡啶酮支架是一种新型化学型，有望开发抗结核药物。