Rational Design and Antimycobacterial Evaluation of Aryl Sulfonamide-Linked Isoniazid Hydrazones Against Mycobacterium Tuberculosis.

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-09-17 DOI:10.1002/cmdc.202500398
Mukanda Gedeon Kadima, Sahil Mishra, Gobind Kumar, Pule Seboletswe, Afsana Kajee, Ankit, Françoise Roquet-Banères, Maëlle Foubert, Laurent Kremer, Rajshekhar Karpoormath, Parvesh Singh
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Abstract

Despite significant advancements in antituberculosis (TB) drug discovery, considerable scope remains for novel therapeutic development. Molecular hybridization represents a promising strategy for generating new anti-TB agents. In this study, in silico molecular docking is employed to design novel isoniazid-sulfonamide hybrids connected via a hydrazone bridge, designated as series 7j-r and 8a-i. Docking analysis reveals that these compounds interact significantly with the active site of InhA, particularly engaging the catalytic triad residues Y158, F149, and K165, as well as the cofactor NAD. Subsequently, both series are synthesized and evaluated against Mycobacterium tuberculosis. Generally, compounds from both series (7 and 8) exhibit enhanced activity compared to their precursors. Notably, compound 8a demonstrated approximately twofold greater potency ( minimum inhibitory concentration (MIC) = 0.156 µg mL-1) with respect to compound 7j (MIC = 0.313 µg mL-1). However, these compounds lose efficacy against INH-resistant M. tuberculosis strains harboring katG mutations and remain ineffective against multidrug-resistant and extensively drug-resistant strains of M. tuberculosis. Encouragingly, the tested compounds exhibit little cytotoxicity against the THP-1 human monocytic cell line at a concentration of 20 µg mL-1. Additionally, the structural stability studies using 1H NMR confirm the structural integrity of these compounds. Overall, these molecular hybrids are promising for further development as anti-TB agents after relevant structural optimizations.

芳基磺胺联异烟肼腙抗结核分枝杆菌的合理设计及抑菌效果评价。
尽管抗结核(TB)药物的发现取得了重大进展,但仍有相当大的空间用于开发新的治疗方法。分子杂交是产生新的抗结核药物的一种很有前途的策略。本研究采用硅分子对接的方法,设计了通过腙桥连接的新型异烟肼-磺胺杂化物,命名为7j-r和8a-i系列。对接分析表明,这些化合物与InhA活性位点有明显的相互作用,特别是与催化三联体残基Y158、F149和K165以及辅因子NAD结合。随后,合成了这两个系列并对结核分枝杆菌进行了评价。通常,这两个系列的化合物(7和8)都比它们的前体表现出更强的活性。值得注意的是,化合物8a的最低抑菌浓度(MIC)为0.156µg mL-1,是化合物7j的两倍(MIC = 0.313µg mL-1)。然而,这些化合物对含有katG突变的inh耐药结核分枝杆菌菌株失去效力,对多药耐药和广泛耐药结核分枝杆菌菌株仍然无效。令人鼓舞的是,在浓度为20 μ g mL-1时,所测试的化合物对THP-1人单核细胞系表现出很小的细胞毒性。此外,利用1H NMR进行的结构稳定性研究证实了这些化合物的结构完整性。综上所述,这些分子杂交体经过结构优化后,具有进一步开发抗结核药物的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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