合理设计的InhA抑制剂:异烟肼磺酸酯及其结构柔性苯类似物抗结核活性的比较研究

IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mukanda Gedeon Kadima, Sahil Mishra, Gobind Kumar, Pule Seboletswe, Françoise Roquet-Banères, Maëlle Foubert, Laurent Kremer, Rajshekhar Karpoormath, Parvesh Singh
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引用次数: 0

摘要

异烟肼与疏水芳香基团的分子杂交是开发新型抗结核药物的一个有前途的策略。本研究通过腙桥接异烟肼与芳香磺酸酯,合成了一系列杂化分子5a-i。分子对接研究表明,这些化合物与InhA酶的催化三元体(Y158, F149和K165)有效相互作用,表明它们具有作为InhA抑制剂的潜力。为了增强分子柔韧性,改善与NADH和催化残基的结合相互作用,设计并合成了第二代衍生物(8a-k)。所有合成的化合物都使用光谱技术进行了结构表征,包括核磁共振(NMR)、傅里叶变换红外光谱(IR)和高分辨率质谱。正如预期的那样,这些新化合物与它们的前体相比显示出增强的抗结核活性。值得注意的是,化合物8b对结核分枝杆菌(Mtb)的MIC为0.078 μg/mL,比其前体5b (MIC = 0.156 μg/mL)的活性高约两倍。然而,两代化合物(例如,5a、5b、8a、8b、8c和8k)对携带katG突变的耐inh结核分枝杆菌菌株失去了活性。重要的是,这些化合物在浓度为10 μg/mL的THP-1人单核细胞中未观察到细胞毒性。通过1H NMR稳定性研究证实了先导化合物8b的结构完整性。还探讨了ADME/T参数(吸收、分布、代谢、排泄和毒性),以确定它们的药物相似性和安全性。总的来说,这些杂交分子为进一步优化新的抗结核药物提供了有价值的支架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Rationally Designed InhA Inhibitors: A Comparative Anti-Tubercular Activity Study of Sulfonate Esters of Isoniazid Hydrazones and Their Structurally Flexible Benzyl Analogues

Rationally Designed InhA Inhibitors: A Comparative Anti-Tubercular Activity Study of Sulfonate Esters of Isoniazid Hydrazones and Their Structurally Flexible Benzyl Analogues

Molecular hybridization of isoniazid with hydrophobic aromatic moieties represents a promising strategy for the development of novel anti-tubercular therapeutics. In this study, a series of hybrid molecules (5a–i) was synthesized by linking isoniazid with aromatic sulfonate esters via a hydrazone bridge. Molecular docking studies revealed that these compounds interact effectively with the catalytic triad of the InhA enzyme (Y158, F149, and K165), suggesting their potential as InhA inhibitors. To enhance molecular flexibility and improve binding interactions with both NADH and the catalytic residues, a second generation of derivatives (8a–k) was designed and synthesized. All synthesized compounds were structurally characterized using spectroscopic techniques, including nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (IR), and high-resolution mass spectrometry. As anticipated, these new compounds exhibited enhanced anti-tubercular activity compared to their precursors. Notably, compound 8b demonstrated significant potency with an MIC of 0.078 μg/mL, approximately twofold more active than its precursor 5b (MIC = 0.156 μg/mL) against Mycobacterium tuberculosis (Mtb). However, both generations of compounds (e.g., 5a, 5b, 8a, 8b, 8c, and 8 k) lost activity against INH-resistant Mtb strains harboring katG mutations. Importantly, no cytotoxicity was observed for these compounds in THP-1 human monocytic cells at a concentration of 10 μg/mL. The structural integrity of the lead compound 8b was confirmed via 1H NMR stability studies. The ADME/T parameters (absorption, distribution, metabolism, excretion, and toxicity) were also explored to determine their drug likeness and safety profile. Collectively, these hybrid molecules present valuable scaffolds for further optimization in the pursuit of new anti-tubercular agents.

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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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