The natural-based optimization of kojic acid conjugated to different thio-quinazolinones as potential anti-melanogenesis agents with tyrosinase inhibitory activity

Melanin pigment and melanogenesis are a two-edged sword. Melanin has a radioprotection role while melanogenesis has undesirable effects. Targeting the melanogenesis pathway, a series of kojyl thioether conjugated to different quinazolinone derivatives were designed, synthesized, and evaluated for their inhibitory activity against mushroom tyrosinase. All the synthesized compounds were screened for their anti-tyrosinase activity and all derivatives displayed better potency than kojic acid as the positive control. In this regard, 5j and 5h as the most active compounds showed an IC50 value of 0.46 and 0.50 ?M, respectively. In kinetic evaluation against tyrosinase, 5j depicted an uncompetitive inhibition pattern. Designed compounds also exhibited mild antioxidant capacity. Moreover, 5j and 5h achieved good potency against the B16F10 cell line to reduce the melanin content, whilst showing limited toxicity against malignant cells. The proposed binding mode of new inhibitors evaluated through molecular docking was consistent with the results of structure?activity relationship analysis.

Automated summary

Melanin and melanogenesis have dual roles in radioprotection and undesirable effects, while designed compounds show potent inhibition of melanogenesis and tyrosinase activity, along with mild antioxidant capacity. Compound 5j and 5h exhibit the best inhibitory activity and reduce melanin content in B16F10 cells with limited toxicity against malignant cells. The proposed binding mode of new inhibitors through molecular docking is consistent with structure-activity relationship analysis.