摘要
目的本研究旨在合成和表征嘧啶连接的苯并咪唑杂环化合物,确定其体外抗微生物和抗真菌活性,并测定其抑制新冠病毒主要蛋白酶和刺突糖蛋白的能力。方法利用分子对接技术,通过评估苯并咪唑杂环合成化合物与酶的变构位点的结合方式,研究其抑制新冠病毒主要蛋白酶和刺突糖蛋白的能力。通过光谱分析验证了微波辅助合成的嘧啶连接苯并咪唑衍生物的结构。通过肉汤稀释法测定其抗细菌和抗真菌活性。结果革兰氏阴性大肠杆菌和铜绿假单胞菌对这些衍生物的敏感性高于革兰氏阳性金黄色葡萄球菌和化脓性链球菌。白色念珠菌在最低抑菌浓度250μg/mL下对这些衍生物敏感。相比目前作为新冠病毒感染疗法进行研究的奈非那韦、洛匹那韦、伊维菌素、瑞德西韦和法匹拉韦,这些新型衍生物具有更好的结合亲和力(kcal/mol),目前正在研究这些药物治疗新冠病毒感染。化合物2c、2e和2g与主蛋白酶的活性空腔形成四个氢键。许多衍生物对新冠病毒刺突糖蛋白的受体结合域(RBD)具有良好的结合亲和力,最多可形成四个氢键。结论我们合成了一些新型的嘧啶连接苯并咪唑衍生物,它们是强效的抗微生物制剂,具有抑制新冠病毒刺突糖蛋白的能力。了解主要蛋白酶和刺突糖蛋白的药效团特征为开发更强效的药物提供了广阔空间。我们计划使用体内和体外模型优化这些衍生物的性质,使它们成为更有效的抗细菌和新冠病毒感染的治疗选择。
Objective The study aimed to synthesize and characterize pyrimidine-linked benzimidazole hybrids,define their antimicrobial and antifungal activities in vitro,and determine their ability to inhibit the main protease and spike glycoprotein of SARS-CoV-2.Methods The ability of the synthesized compounds to inhibit the main protease and spike glycoprotein inhibitory of SARS-CoV-2 was investigated by assessing their mode of binding to the allosteric site of the enzyme using molecular docking.The structures of pyrimidine-linked benzimidazole derivatives synthesized with microwave assistance were confirmed by spectral analysis.Antibacterial and antifungal activities were determined by broth dilution.Results Gram-negative bateria(Escherichia coli and Pseudomonas aeruginosa)were more sensitive than gram-positive bateria(Staphylococcus aureus and Streptococcus pyogenes)to the derivatives.Candida albicans was sensitive to the derivatives at a minimal inhibitory concentration(MIC)of 250μg/mL.The novel derivatives had better binding affinity(kcal/mol)than nelfinavir,lopinavir,ivermectin,remdesivir,and favipiravir,which are under investigation as treatment for SARS-CoV-2 infection.Compounds 2c,2e,and 2g formed four hydrogen bonds with the active cavity of the main protease.Many derivatives had good binding affinity for the RBD of the of SARS-CoV-2 spike glycoprotein with the formation of up to four hydrogen bonds.Conclusion We synthesized novel pyrimidine-linked benzi-midazole derivatives that were potent antimicrobial agents with ability to inhibit the SARS-CoV-2 spike glycoprotein.Understanding the pharmacophore features of the main protease and spike glycoprotein offers much scope for the development of more potent agents.We plan to optimize the properties of the derivatives using models in vivo and in vitro so that they will serve as more effective therapeutic options against bacterial and SARS-CoV-2 infections.
