Hekal Hend A, Salem Maha M, El Salam Hayam A Abd
Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
BMC Chem. 2024 Sep 18;18(1):174. doi: 10.1186/s13065-024-01268-2.
Heterocyclic compounds play a crucial role in the drug discovery process and development due to their significant presence and importance. Here, we report a comprehensive analysis of α-aminophosphonates containing pyridine (3a-g), prepared according to a clear-cut, uncomplicated procedure. The phosphonates are thoroughly characterized using various methods, such as elemental analysis, mass spectrometry, proton and carbon NMR, and FT-IR. The molecular docking interactions between the phosphonate and DRP-1 target protein observed that compound 3d had the top-ranked binding energy towards DRP-1 with a value equal to - 9.54 kcal/mol and this theoretically proves its inhibitory efficacy against DRP-1 arbitrated mitochondrial fission. Besides, the anticancer characteristics of compound 3d showed the best IC against HepG-2, MCF-7, and Caco-2 which confirmed our results towards suppressing DRP-1 protein (in-silico), and it elucidated no cytotoxic effects against human normal cell line (WI-38). Further, its pharmacokinetics were observed theoretically using ADMET. Moreover,compound 3d investigated the most potent antimicrobial ability against two pathological fungal strains, A. flavus and C. albicans, and four bacterial strains, E. coli, B. subtillis, S. aureus, and P. aregeunosa. Additionally, compound 3d clarified a powerful antioxidant scavenging activity against DPPH and ABTS free radicals (in-vitro). Furthermore, Density functional theory (DFT) was used to study the molecular structures of the synthesized compounds 3a-g, utilizing 6-311++G(d,p) as the basis set and to learn more about the molecules' reactive sites, the energies of the molecular electrostatic potential (MEP), the lowest unoccupied molecular orbital (LUMO), and the highest occupied molecular orbital (HOMO) were observed. Theoretically, FT-IR and Nuclear magnetic resonance (NMR) measurements are calculated for every compound under investigation to show how theory and experiment relate. It was found that there was an excellent agreement between the theoretical and experimental data. Conclusively, all novel synthesized phosphonates could be used as pharmaceutical agents against pathogenic microbial strains and as anticancer candidates by inhibiting DRP-1-mediated mitochondrial mitophagy.
杂环化合物因其大量存在和重要性在药物发现过程与开发中发挥着关键作用。在此，我们报告了对含吡啶的α-氨基膦酸酯（3a - g）的全面分析，其通过明确、简单的程序制备。这些膦酸酯使用多种方法进行了全面表征，如元素分析、质谱、质子和碳核磁共振以及傅里叶变换红外光谱。膦酸酯与DRP - 1靶蛋白之间的分子对接相互作用表明，化合物3d对DRP - 1具有最高排名的结合能，值为 - 9.54千卡/摩尔，这从理论上证明了其对DRP - 1介导的线粒体分裂的抑制功效。此外，化合物3d的抗癌特性显示对HepG - 2、MCF - 7和Caco - 2具有最佳的半数抑制浓度（IC），这证实了我们在抑制DRP - 1蛋白方面的结果（计算机模拟），并且阐明了其对人正常细胞系（WI - 38）无细胞毒性作用。此外，使用ADMET理论观察了其药代动力学。而且，化合物3d对两种致病真菌菌株黄曲霉和白色念珠菌以及四种细菌菌株大肠杆菌、枯草芽孢杆菌、金黄色葡萄球菌和嗜麦芽窄食单胞菌表现出最强的抗菌能力。此外，化合物3d在体外对二苯基苦味酰基自由基（DPPH）和2,2'-联氮-双-3-乙基苯并噻唑啉-6-磺酸自由基（ABTS）表现出强大的抗氧化清除活性。此外，利用密度泛函理论（DFT），以6 - 311++G(d,p)为基组研究了合成化合物3a - g的分子结构，并观察了分子静电势（MEP）能量、最低未占分子轨道（LUMO）和最高占据分子轨道（HOMO），以更多地了解分子的反应位点。理论上，对每个研究的化合物计算了傅里叶变换红外光谱（FT - IR）和核磁共振（NMR）测量值，以展示理论与实验的关系。发现理论数据与实验数据之间有很好的一致性。总之，所有新合成的膦酸酯可通过抑制DRP - 1介导的线粒体自噬用作抗病原微生物菌株的药物制剂和抗癌候选物。
