Mujeeb Samar, Singh Kuldeep, Al-Zrkani Martha K, Al-Fahad Dhurgham, Hasan Syed Misbahul, Shouber Marwah Al, Ahmad Fuzail, Hameed Husian Njem, Iqbal Danish, Kamal Mehnaz
Department of Pharmaceutical Chemistry, Hygia Institute of Pharmaceutical Education &Research, Lucknow, Uttar Pradesh 226020, India.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh 226026, India.
Bioorg Chem. 2025 Apr;157:108249. doi: 10.1016/j.bioorg.2025.108249. Epub 2025 Feb 7.
Tuberculosis (TB) continues to pose a significant public health challenge worldwide. Hydrazide-containing compounds have demonstrated considerable potential as anti- tubercular agents. In this study, we designed, synthesized, and evaluated a series of chroman- Schiff base derivatives, integrating a chroman scaffold with substituted phenyl moieties, as potential therapeutic candidates against TB. In silico studies were conducted to assess the binding interactions of the synthesized derivatives, specifically their R- and S-isomers, with the tuberculosis target protein InhA (PDB ID: 1ZID). Molecular docking revealed that two R-isomer derivatives, SM-5A and SM-6A, exhibited superior binding affinities (-10.6 kcal/mol) compared to the reference ligand INH-NADH (-10.3 kcal/mol) and the natural substrate NADH (-7.5 kcal/mol). Molecular dynamics simulations confirmed the long-term stability of these compound-protein complexes over a 100 ns trajectory, further substantiating their potential as stable inhibitors. The structures of the synthesized derivatives were validated using spectroscopic techniques, including FTIR, C NMR, H NMR, and HR-MS. Biological evaluation via in vitro anti-tubercular assays against Mycobacterium tuberculosis HRv (using the Microplate Alamar Blue Assay) demonstrated that several RRR-isomers displayed notable activity. Among them, SM-2 and SM-5 showed the most potent effects, with minimum inhibitory concentrations (MIC) of 32 µg/mL, comparable to standard anti-tubercular drugs such as isoniazid, ethambutol, and rifampicin. These findings highlight the chroman-schiff base scaffold as a promising foundation for the development of novel anti-tubercular agents. The integration of computational and experimental approaches in this study underscores the potential of these derivatives for further optimization and development into effective anti-tubercular therapeutics.
结核病（TB）在全球范围内仍然是一项重大的公共卫生挑战。含肼化合物已显示出作为抗结核药物的巨大潜力。在本研究中，我们设计、合成并评估了一系列苯并二氢吡喃 - 席夫碱衍生物，将苯并二氢吡喃支架与取代苯基部分相结合，作为潜在的抗结核治疗候选物。进行了计算机模拟研究，以评估合成衍生物，特别是其R - 和S - 异构体与结核靶点蛋白InhA（PDB ID：1ZID）的结合相互作用。分子对接显示，与参考配体INH - NADH（-10.3 kcal/mol）和天然底物NADH（-7.5 kcal/mol）相比，两种R - 异构体衍生物SM - 5A和SM - 6A表现出更高的结合亲和力（-10.6 kcal/mol）。分子动力学模拟证实了这些化合物 - 蛋白质复合物在100 ns轨迹上的长期稳定性，进一步证实了它们作为稳定抑制剂的潜力。使用包括FTIR、¹³C NMR、¹H NMR和HR - MS在内的光谱技术对合成衍生物的结构进行了验证。通过针对结核分枝杆菌HRv的体外抗结核试验（使用微孔板阿拉玛蓝试验）进行的生物学评估表明，几种RRR - 异构体表现出显著活性。其中，SM - 2和SM - 5显示出最有效的效果，最低抑菌浓度（MIC）为32 μg/mL，与异烟肼、乙胺丁醇和利福平之类的标准抗结核药物相当。这些发现突出了苯并二氢吡喃 - 席夫碱支架作为开发新型抗结核药物的有前景的基础。本研究中计算和实验方法的结合强调了这些衍生物进一步优化并开发成有效抗结核治疗药物的潜力。
