Unveiling the Potential of Isoquinoline-Tethered 1,2,3-Triazoles as Promising Anti-Biofilm Agents Against Candida albicans: Synthesis, Biological Evaluation, ADME, and Molecular Docking Studies.

A library of twelve new 1-phenyl-1,2,3,4-tetrahydroisoquinoline tethered 1-phenyl-1H-1,2,3-triazol-4-yl-methyl derivatives 7(a-l) were synthesized via copper-catalyzed azide alkyne cycloaddition. The synthesized derivatives were characterized by 1H-NMR, 13C-NMR, and mass spectrometry techniques. All the derivatives were screened for in vitro antifungal activity against an opportunistic pathogen Candida albicans by broth microdilution method. The study revealed that compound 7i exhibited the potent antifungal profile with minimum inhibitory concentration (MIC) of 6 µg/mL, minimum fungicidal concentration (MFC) of 32 µg/mL, and it demonstrated 82% biofilm inhibition and 78% filament inhibition. The results showed an improvement over the standard drug fluconazole which exhibited MIC of 8 µg/mL and MFC of 64 µg/mL, 78% biofilm inhibition, and 65% of filament inhibition. Further the inhibition was confirmed by SEM analysis and qRT-PCR was conducted against HWP1, EFG1, and ALS3 genes. In addition, an in silico molecular docking study was carried out to demonstrate the interactions between the synthesized compounds and target amino acids. ADMET analysis indicated all the compounds met the criteria of drug-likeness and follow Lipinski's rule of five. Further optimization of these derivatives could yield promising therapeutics for Candidal infections.