Abstract

Antimicrobial resistance has become a significant threat to global public health, thus precipitating an exigent need for new drugs with improved therapeutic efficacy. In this regard, molecular hybridization is deemed as a viable strategy to afford multi-target-based drug candidates. Herein, we report a library of quinoline—1H-1,2,3-triazole molecular hybrids synthesized via copper(I)-catalyzed azide-alkyne [3 + 2] dipolar cycloaddition reaction (CuAAC). Antimicrobial evaluation identified compound 16 as the most active hybrid in the library with a broad-spectrum antibacterial activity at an MIC₈₀ value of 75.39 μM against methicillin-resistant S. aureus, E. coli, A. baumannii, and multidrug-resistant K. pneumoniae. The compound also showed interesting antifungal profile against C. albicans and C. neoformans at an MIC₈₀ value of 37.69 and 2.36 μM, respectively, superior to fluconazole. In vitro toxicity profiling revealed non-hemolytic activity against human red blood cells (hRBC) but partial cytotoxicity to human embryonic kidney cells (HEK293). Additionally, in silico studies predicted excellent drug-like properties and the importance of triazole ring in stabilizing the complexation with target proteins. Overall, these results present compound 16 as a promising scaffold on which other molecules can be modeled to deliver new antimicrobial agents with improved potency.

Graphic abstract

中文翻译：

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喹啉-1H-1,2,3-三唑分子杂化物的合成、抗菌评估和计算机研究。

 抽象的

抗生素耐药性已成为全球公共卫生的重大威胁，因此迫切需要具有改善疗效的新药。在这方面，分子杂交被认为是提供基于多靶点的候选药物的可行策略。在此，我们报道了通过铜（I）催化的叠氮化物-炔[3 + 2]偶极环加成反应（CuAAC）合成的喹啉-1 H -1,2,3-三唑分子杂化物库。抗菌评估确定化合物16是文库中最活跃的杂合体，对耐甲氧西林金黄色葡萄球菌、大肠杆菌、鲍曼不动杆菌和多重耐药克鲁克杆菌具有广谱抗菌活性，MIC ₈₀值为 75.39 μM。肺炎杆菌。该化合物还对白色念珠菌和新型念珠菌表现出令人感兴趣的抗真菌特性，MIC ₈₀值分别为 37.69 和 2.36 μM，优于氟康唑。体外毒性分析显示对人红细胞 (hRBC) 无溶血活性，但对人胚胎肾细胞 (HEK293) 有部分细胞毒性。此外，计算机研究预测了优异的药物样特性以及三唑环在稳定与靶蛋白的络合方面的重要性。总体而言，这些结果表明化合物16作为一种有前途的支架，可以在其上模拟其他分子以提供具有改进效力的新抗菌剂。

 图文摘要