Exploring the Mechanisms of Indole-Oxadiazole Benzamide Hybrids as Tyrosinase Inhibitors: Insights from Lineweaver-Burk Plot Analysis and Computational Studies

Objective: This study aimed to synthesize hybrid compounds incorporating indole, oxadiazole, and benzamide moieties, leveraging their known biological activities, to evaluate their potential as tyrosinase inhibitors. Methods: A convergent synthetic approach was employed to develop the hybrid compounds. Structural confirmation was achieved through infrared spectroscopy (IR), proton nuclear magnetic resonance (1H NMR), carbon nuclear magnetic resonance (13C NMR), and elemental analysis (CHN). The inhibitory effects on tyrosinase were assessed using enzyme kinetics, with Lineweaver-Burk plots utilized to determine the mechanism of inhibition. Results and Discussion: The synthesized bi-heterocyclic benzamides demonstrated excellent inhibitory activities against tyrosinase compared to the standard control. Compound (VIIIf) exhibited non-competitive inhibition, forming an enzyme-inhibitor complex, with an inhibition constant (Ki) of 0.0033 µM. Computational analysis indicated favorable binding energy values for these compounds. The study highlights the promising potential of these hybrid molecules as effective tyrosinase inhibitors. The structure-activity relationship analysis suggests that the incorporation of indole, oxadiazole, and benzamide moieties enhances the inhibitory efficacy against tyrosinase, which is crucial for developing treatments for skin disorders. Conclusions: The synthesized indole-oxadiazole-benzamide hybrids are identified as potent tyrosinase inhibitors with significant potential as medicinal scaffolds for treating skin conditions. Further investigations into their therapeutic applications are warranted.