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 ( 1 H NMR), carbon nuclear magnetic resonance ( 13 C 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 ( K i ) 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.