Synthesis, in vitro and in silico studies of diarylpentadienone analogues as anti-tyrosinase and anti-melanogenic agents

Hyperpigmentation, a common skin concern, affects the facial aesthetics and skin tone uniformity. Although there are many treatment options, safety remains a concern. Curcumin offers a safer alternative due to its antimelanogenic and antioxidant properties, but is limited by its poor bioavailability and instability. To overcome these drawbacks, curcumin-derived diarylpentadienones were synthesised and evaluated as potential skin lightening agents. In this study, a series of new diarylpentadienones were first tested against mushroom tyrosinase monophenolase and diphenolase assays. The new compounds 10 and 21 demonstrated strong diphenolase inhibition with IC50 values of 0.46 +/- 0.43 and 9.53 +/- 0.69 mu M, respectively, outperforming kojic acid (10.33 +/- 0.22 mu M). Kinetic studies showed that both compounds act as competitive inhibitors. Cellular cytotoxicity assays confirmed their safety and showed no significant toxicity up to 25 mu M for compound 10 and 50 mu M for compound 21. In B16-F10 murine melanoma cells, both compounds significantly reduced melanin content and tyrosinase activity at 25 mu M. In addition, the expression of key melanogenesis genes (tyr, tyr-1 and mtif) was downregulated by treatment with diarylpentadienones. Structure-activity relationship analysis showed that a 4 '-fluorophenyl group in combination with a 4-hydroxyphenyl or 4-methoxyphenyl moiety enhanced the anti-tyrosinase activity. Molecular docking confirmed the involvement of these groups in key interactions with the active site residues of tyrosinase. Collectively, these results highlight compounds 10 and 21 as promising anti-tyrosinase and antimelanogenic agents that warrant further in vivo studies and mechanistic exploration for potential application in cosmetic skin care formulations.