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

In 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 & PLUSMN;3.64 & mu;M, 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. In this work, a series of chalcone-based 2-arylidene-1,3-indandione was synthesized, and evaluated for their inhibitory activities against the mushroom tyrosinase enzyme. Among them, compound 6 l presented superior activity with an IC50 value of 15.85 & PLUSMN;3.64 & mu;M as an uncompetitive inhibitor, which was lower than the standard kojic acid. Next, the docking study exhibited compound 6 l formed hydrogen bonds and hydrophobic interactions with critical highly conserved amino acids in the target protein with a stable ligand-enzyme complex during the dynamics simulation.image

Automated summary

A series of chalcone-based 2-arylidene-1,3-indandione was synthesized and evaluated for their inhibitory activities against the mushroom tyrosinase enzyme. Among them, compound 6 l exhibited superior activity as an uncompetitive inhibitor with an IC50 value of 15.85±3.64μM, which was lower than the standard kojic acid. Docking study showed compound 6 l formed hydrogen bonds and hydrophobic interactions with critical highly conserved amino acids, and molecular dynamics simulation confirmed the stability of the ligand-enzyme complex.