7-Methoxybenzofuran-triazole tethered <i>N</i>-phenylacetamides as a promising class of tyrosinase inhibitors: synthesis, biological evaluation and computational analyses against fungal and human tyrosinases

Aberrant melanogenesis results in excessive melanin production, which may lead to hyperpigmentation and related disorders. There has been extensive ongoing research to develop novel tyrosinase inhibitors as excessive activity of tyrosinase enzymes causes surplus production of melanin. Herein, we have evaluated the tyrosinase inhibition potency of a novel series of 7-methoxybenzofuran-joined <i>N</i>-phenylacetamides 16(a-j) (synthesized in a 62-90% yield range) <i>via in vitro</i> and <i>in silico</i> analyses. The entire set of prepared derivatives 16(a-j) demonstrated excellent inhibition potential, even more efficacious than the employed standards, <i>i.e.</i>, kojic and ascorbic acid (exhibiting IC₅₀ values of 30.34 ± 1.00 μM and 11.5 ± 1.00 μM, respectively). Among the synthesized hybrids 16(a-j), <i>N</i>-(2-methoxyphenyl)acetamide linked benzofuran derivative 16h was determined to be the most promising tyrosinase inhibitor (with IC₅₀ = 0.39 ± 1.45 μM), followed by <i>N</i>-(3-nitrophenyl)acetamide linked benzofuran derivative 16f (with IC₅₀ = 0.76 ± 1.71 μM). <i>In vitro</i> assay findings were further authenticated by docking the potent compounds along with the standards against fungal tyrosinase. Furthermore, assessment of the tyrosinase inhibition potency of the promising hybrids 16h and 16f was carried out against human tyrosinase. The docking findings for potent hybrid 16h were supported by performing molecular dynamics simulation studies, emphasizing its potent and stable interactions with fungal and human tyrosinases in comparison to the chosen standards, <i>i.e.</i>, kojic and ascorbic acid.