Antimicrobial activity and antifungal mechanistic study of 3‑substituted oxindoles against Aspergillus niger

A series of 3-substituted oxindole derivatives 3a-j was synthesized. The target compounds 3a-j were investigated for their potential antibacterial and antifungal activities. S. aureus, MRSA, E. faecalis, P. aeruginosa, K. pneumonia, and E. coli were used for testing the antibacterial activity, while Candida albicans and Aspergillus spp, were used for antifungal activity of the tested compounds. Compounds 3i and 3j exhibited the strongest activity, particularly against Gram-positive bacteria. Antifungal activity was tested against Aspergillus spp. and Candida albicans using the agar diffusion method, with a final concentration of 10,000 µg/mL per well. Eight compounds inhibited Aspergillus spp., while only compound 3g was active against C. albicans. Compound 3f displayed the highest antifungal activity (inhibition zone = 20 mm) compared with itraconazole with a final concentration of 100 µg/mL per well (30 mm). Minimum inhibitory concentration (MIC) testing confirmed compound 3f as the most potent antifungal, with an MIC of 7.5 µg/mL against Aspergillus niger, lower than that of clotrimazole (12.5 µg/mL). Further investigations showed that compound 3f exerted its effect by disrupting fungal cell wall integrity without binding ergosterol. Docking studies of compound 3f in the active sites of chitin deacetylase AngCDA (PDB ID: 7BLY) and the 1,3-β-glucan synthase (8JZN) enzymes proved its dual-target mechanism ability to inhibit the cell wall biosynthesis. These findings highlight compound 3f as a promising lead scaffold for the development of new antifungal agents targeting fungal cell wall biosynthesis.