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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引用次数: 0

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.

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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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