Synthesis and Antimicrobial Evaluation of 1H-1,2,3-Triazole-Linked Quinoline-Phenolic Natural Product Conjugates

A new library of quinoline–natural product conjugates bearing 1,2,3-triazole moiety as a linker has been synthesized using the copper(I) catalyzed azide-alkyne [3 + 2] cycloaddition reaction (CuAAC) methodology. The structure characterization of the synthesized compounds was achieved using NMR and HRMS analysis. The compounds were subsequently screened for their antimicrobial efficacies against methicillin resistant Staphylococcus aureus (MRSA), MDR Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and Cryptococcus neoformans. The studied compounds generally displayed stronger inhibition of microbial cell growth compared to their parent phenolic natural products. Eugenol, thymol, guaiacol, and o-vanillin based 1H-1,2,3-triazole compounds exhibited the best antimicrobial profiles while the pathogen, A. baumannii showed the highest susceptibility to the hybrids. Precisely, hybrids 19a, 20b, and 25b derived from eugenol, thymol, and o-vanillin, respectively, exhibited over 50% growth inhibition of the pathogen. K. pneumoniae was however strongly resistant to the compound series. In silico docking studies of the representative compounds further explored the characteristic binding orientations of these compounds in the active sites of the bacterial and fungal proteins. Overall, we perceive that rational scaffold hopping of these compounds holds promise to offer novel antimicrobial agents with enhanced potency.