Design, Synthesis, and Molecular Dynamics Simulation Studies of New Chalcone‐Based 2‐Arylidene‐1,3‐indandiones as Tyrosinase Inhibitors

Abstract

AbstractIn this work, we synthesized a series of chalcone‐based 2‐arylidene‐1,3‐indandione and evaluated their inhibitory activities against the mushroom tyrosinase enzyme. Based on benzylidene moiety, derivatives were divided into 4‐benzyloxy‐benzylidene and 4‐benzyloxy‐3‐methoxy‐benzylidene derivatives. Among them, 2‐(3‐methoxy‐4‐((4‐methylbenzyl)oxy)benzylidene)‐1H‐indene‐1,3(2H)‐dione (6 l) was presented the superior activity with an IC50 value of 15.85±3.64 μM, which was lower than the standard kojic acid. The kinetic study of compound 6 l displayed an uncompetitive inhibition mode on the tyrosinase enzyme. Next, the docking study exhibited compound 6 l formed hydrogen bonds and hydrophobic interactions with critical highly conserved amino acids in the target protein. Furthermore, based on the molecular dynamics simulation, compound 6 l depicted noticeable interaction with the essential residues of the binding site and exhibited a stable complex during the simulation run. The methoxy group on the central ring was important in inducing the effective conformation for ligand‐enzyme interaction. The drug‐likeness and pharmacokinetic properties were calculated via in silico predictions and showed an acceptable profile for these agents. According to our results, it was proposed that compound 6 l can serve as a drug candidate to develop more potent antityrosinase agents.