Isoniazid-Dihydropyrimidinone Molecular Hybrids: Design, Synthesis, Antitubercular Activity, and Cytotoxicity Investigations with Computational Validation.

IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-03-11 DOI:10.1002/cmdc.202400949
Gobind Kumar, Pule Seboletswe, Sahil Mishra, Neha Manhas, Safiyah Ghumran, Nagaraju Kerru, Françoise Roquet-Banères, Maëlle Foubert, Laurent Kremer, Gaurav Bhargava, Parvesh Singh
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Abstract

A new series of isoniazid-dihydropyrimidinone molecular hybrids (8a-8n) were designed, synthesized and structurally characterized using different spectroscopic techniques viz., Fourier transform infrared spectroscopy, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry followed by their antitubercular evaluation including their precursors (4a-4n), and a standard antitubercular drug (isoniazid; INH). The molecular hybrids particularly 8g (minimum inhibitory concentration (MIC) = 6.25 μg mL-1), 8h (MIC = 1.56 μg mL-1), 8k (MIC = 0.78 μg mL-1), 8l (MIC = 6.25 μg mL-1), and 8n (MIC = 0.39 μg mL-1) demonstrated the most potent inhibitory activity against wild-type M. tuberculosis mc26230, disclosing 8n as the most potent compound in the series. However, the potent compounds lost their activity against three INH-resistant M. tuberculosis strains mutated in katG. The more efficient compounds (8h, 8k, and 8n) were subsequently evaluated for their cytotoxicity against the THP-1 human monocytic cell line. Furthermore, the stability studies of the most potent compound carried out using 1H NMR, UV-visible, and liquid chromatography-mass spectrometry revealed their structural integrity. Finally, in silico molecular docking simulations were conducted to explore the binding orientations of the potent compounds in the active site of the target protein InhA while ADME/T (absorption, distribution, metabolism, excretion, and toxicity) and global reactivity parameters were explored to determine their drug-likeness and stability profiles, respectively.

异烟肼-二氢嘧啶分子杂合体:设计、合成、抗结核活性和细胞毒性研究与计算验证。
在本研究中,我们设计并合成了一系列新的异烟肼-二氢嘧啶分子杂合体(8a-8n)。利用FTIR、NMR (1H、13C、HMBC和HSQC)和HRMS等光谱技术对所有化合物进行结构表征,然后进行体外抗结核评价,包括其前体(4a-4n)和标准抗结核药物(异烟肼;异烟肼)。其中8g (MIC = 6.25µg/ml)、8h (MIC = 1.56µg/ml)、8k (MIC = 0.78µg/ml)、8l (MIC = 6.25µg/ml)和8n (MIC = 0.39µg/ml)对野生型结核分枝杆菌mc26230的抑制活性最强,表明8n是该系列化合物中抑制活性最强的化合物。然而,对野生型菌株MIC值较低的有效化合物(8g、8h、8k、8l和8n)对3株在katG中突变的耐inh结核分枝杆菌失去了活性。随后评估了更有效的化合物(8h, 8k和8n)对THP-1人单核细胞系的细胞毒性。此外,利用1H NMR, UV-visible和LCMS对最有效的化合物进行了稳定性研究,揭示了它们的结构完整性。综上所述,这些分子杂交体经过相应的结构修饰后,具有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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