Synthesis and Broad-Spectrum Antiviral Evaluation of Novel 1,2,3-Triazole-Quinoline Derivatives Targeting SARS-CoV-2, Influenza, DENV-2, and CHIKV.

The persistent global threat posed by emerging and re-emerging RNA viruses, including SARS-CoV-2, influenza A(H1N1)pdm09, DENV-2, and CHIKV, highlights the critical need for novel and broad-spectrum antiviral agents. Building upon the established antiviral activity of the quinoline scaffold, this study employed a molecular hybridization strategy to design and synthesize a novel series of 1,2,3-triazole-quinoline derivatives (compounds 4a-4h). This approach strategically fused the bioactive quinoline nucleus with the pharmaceutically favorable 1,2,3-triazole ring. The new compounds were synthesized efficiently in three steps with moderate-to-high yields, and their structures were subsequently determined. Their inhibitory capacities against the four viruses and cytotoxicity across relevant cell lines were evaluated in vitro. The initial screening demonstrated that compounds 4a-4h possessed broad-spectrum antiviral activity, showing high inhibition percentages at 10 µM against SARS-CoV-2, DENV-2, and CHIKV. Notably, compounds 4c and 4e, substituted with methoxy and ethyl groups, respectively, displayed exceptional potency and safety against SARS-CoV-2, yielding high selectivity indices (SI: 1896.5 and 1265.8, respectively). Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) and molecular docking calculations suggested favorable drug-likeness profiles, including improved lipophilicity and non-P-glycoprotein substrate feasibility. The findings validate the molecular hybridization strategy, establishing this new class of compounds as promising, multi-target antiviral prototypes for further preclinical exploration against prevalent viral pathogens.