Design and Synthesis of (Z)-2-(Benzylamino)-5-benzylidenethiazol-4(5H)-one Derivatives as Tyrosinase Inhibitors and Their Anti-Melanogenic and Antioxidant Effects

Abstract

In this study, (<i>Z</i>)-2-(benzylamino)-5-benzylidenethiazol-4(5<i>H</i>)-one (BABT) derivatives were designed as tyrosinase inhibitors based on the structure of MHY2081, using a simplified approach. Of the 14 BABT derivatives synthesized, two derivatives ((<i>Z</i>)-2-(benzylamino)-5-(3-hydroxy-4-methoxybenzylidene)thiazol-4(5<i>H</i>)-one [<b>7</b>] and (<i>Z</i>)-2-(benzylamino)-5-(2,4-dihydroxybenzylidene)thiazol-4(5<i>H</i>)-one [<b>8</b>]) showed more potent mushroom tyrosinase inhibitory activities than kojic acid, regardless of the substrate used; in particular, compound <b>8</b> was 106-fold more potent than kojic acid when l-tyrosine was used as the substrate. Analysis of Lineweaver-Burk plots for <b>7</b> and <b>8</b> indicated that they were competitive inhibitors, which was confirmed via in silico docking. In experiments using B16F10 cells, <b>8</b> exerted a greater ability to inhibit melanin production than kojic acid, and it inhibited cellular tyrosinase activity in a concentration-dependent manner, indicating that the anti-melanogenic effect of <b>8</b> is attributable to its ability to inhibit tyrosinase. In addition, <b>8</b> exhibited strong antioxidant activity to scavenge 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals and peroxynitrite and inhibited the expression of melanogenesis-associated proteins (tyrosinase and microphthalmia-associated transcription factor). These results suggest that BABT derivative <b>8</b> is a promising candidate for the treatment of hyperpigmentation-related diseases, owing to its inhibition of melanogenesis-associated protein expression, direct tyrosinase inhibition, and antioxidant activity.