Substituted indole derivatives as antifungal agents: design, synthesis, in vitro and in silico evaluations

Indole derivatives possess various biological activities, including antifungal, antibacterial, anticancer, antioxidant, antimalarial, antidiabetic, antitubercular, and anticholinesterase activities. This study focused on the synthesis of indole and its derivatives using the Fischer indole synthesis method and the Ullmann condensation reaction. The synthesized compound was characterized by melting point determination, UV-spectroscopy, thin layer chromatography, Fourier-transform infrared spectroscopy, and proton nuclear magnetic resonance. The zone of inhibition and the minimum Inhibitory concentration were used to determine antifungal activity against Candida albicans and Aspergillus niger. The parent molecule 2-methyl-1H-indole (B), with a yield of 44% was synthesized by Fischer indole synthesis and Ullmann condensation. Three derivatives of the parent molecules, 3-(2-methyl-1H-indol-1-yl)phenol (A1) with a yield of 68%, 1-(3-(2-methyl-1H-indol-1-yl)phenyl)ethan-1-one (A2) with a yield of 60%, and 2-methyl-1-(3-methylphenyl)-1H-indole (A3) with a yield of 84% were synthesized. Molecular docking revealed that all derivatives bound lanosterol 14α-demethylase more strongly than fluconazole (-7.1 kcal/mol), with A2 showing the highest affinity (-8.1 kcal/mol). (PDBID: 5TZ1). Furthermore, other computational studies through Pass analysis server, Drug likeness prediction by SwissADME, Toxicity prediction by Stoptox, and pkCSM server were performed on synthesized compounds to predict the biological activity. Collectively, these findings highlight indole derivatives, particularly A1 and A2, as promising antifungal leads with potent in vitro efficacy and strong molecular interactions with a clinically validated target.