Identification of (Z)-2-benzylidene-dihydroimidazothiazolone derivatives as tyrosinase inhibitors: Anti-melanogenic effects and in silico studies

Heejeong Choi; Il Young Ryu; Inkyu Choi; Sultan Ullah; Hee Jin Jung; Yujin Park; YeJi Hwang; Yeongmu Jeong; Sojeong Hong; Pusoon Chun; Hae Young Chung; Hyung Ryong Moon

doi:10.1016/j.csbj.2022.02.007

Identification of (Z)-2-benzylidene-dihydroimidazothiazolone derivatives as tyrosinase inhibitors: Anti-melanogenic effects and in silico studies

Comput Struct Biotechnol J. 2022 Feb 12:20:899-912. doi: 10.1016/j.csbj.2022.02.007. eCollection 2022.

Authors

Affiliations

¹ College of Pharmacy, Pusan National University, Busan 46241, South Korea.
² Department of Molecular Medicine, The Scripps Research Institute, FL 33458, USA.
³ College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam 50834, South Korea.

Abstract

As part of our continuous search for novel tyrosinase inhibitors, we designed 5,6-dihydroimindazo[2,1-b]thiazol-3(2H)-one (DHIT) derivatives based on the structure of MHY773; a potent tyrosinase inhibitor with a 2-iminothiazolidin-4-one template. Of the 11 DHIT derivatives synthesized using a Knoevenagel condensation, three DHIT derivatives 1a (IC₅₀ = 36.14 ± 3.90 μM), 1b (IC₅₀ = 0.88 ± 0.91 μM), and 1f (IC₅₀ = 17.10 ± 1.01 μM) inhibited mushroom tyrosinase more than kojic acid (IC₅₀ = 84.41 ± 2.87 μM). Notably, compound 1b inhibited mushroom tyrosinase around 100- and 3.3-fold more potently than kojic acid and MHY773, respectively. Lineweaver-Burk plots demonstrated that compounds 1b and 1f competitively inhibited mushroom tyrosinase, and in silico docking results supported our kinetic results and indicated that these two compounds bind more strongly to the active site of tyrosinase than kojic acid. Docking simulation results using a human tyrosinase homology model confirmed the abilities of 1b and 1f to strongly inhibit human tyrosinase. B16F10 murine melanoma cells were used to investigate whether these two compounds display tyrosinase inhibitory activities and anti-melanogenesis effects in cells. Both compounds were found to significantly and dose-dependently inhibit cellular tyrosinase activity and intracellular and extracellular melanin production more potently than kojic acid. The similarities observed between the cellular tyrosinase and melanogenesis inhibitory effects of 1b and 1f suggest their observed anti-melanogenic effects were due to tyrosinase inhibition. These results indicate that compounds 1b and 1f, which possess the DHIT template, are promising candidates as anti-browning agents and therapeutic agents for hyperpigmentation disorders.

Keywords: (Z)-2-Benzylidene-dihydroimidazothiazolone; Anti-melanogenesis; DHIT template; Docking simulation; Kojic acid; Tyrosinase inhibitor.