Design, Synthesis, and Anti-Melanogenic Activity of 2-Mercaptomethylbenzo[<i>d</i>]imidazole Derivatives Serving as Tyrosinase Inhibitors: An In Silico, In Vitro, and In Vivo Exploration
Hee Jin Jung,
Hyeon Seo Park,
Hye Jin Kim,
Hye Soo Park,
Yujin Park,
Pusoon Chun,
Hae Young Chung,
Hyung Ryong Moon
Affiliations
Hee Jin Jung
Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
Hyeon Seo Park
Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
Hye Jin Kim
Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
Hye Soo Park
Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
Yujin Park
Department of Medicinal Chemistry, New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
Pusoon Chun
College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae 50834, Republic of Korea
Hae Young Chung
Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
Hyung Ryong Moon
Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
2-Mercaptomethylbenzo[d]imidazole (2-MMBI) derivatives were designed and synthesized as tyrosinase (TYR) chelators using 2-mercaptomethylimidazole scaffolds. Seven of the ten 2-MMBI derivatives exhibited stronger inhibition of mushroom TYR activity than kojic acid. Their ability to chelate copper ions was demonstrated through experiments using the copper chelator pyrocatechol violet and assays measuring TYR activity in the presence or absence of exogenous CuSO4. The inhibition mechanisms of derivatives 1, 3, 8, and 9, which showed excellent TYR inhibitory activity, were elucidated through kinetic studies and supported by the docking simulation results. Derivatives 3, 7, 8, and 10 significantly inhibited cellular TYR activity and melanin production in B16F10 cells in a dose-dependent manner, with stronger potency than kojic acid. Furthermore, in situ, derivatives 7 and 10 showed stronger inhibitory effects on B16F10 cell TYR activity than kojic acid. Six derivatives, including 8, showed highly potent depigmentation in zebrafish larvae, outpacing kojic acid even at 200–670 times lower concentrations. Additionally, all derivatives could scavenge for reactive oxygen species without causing cytotoxicity in epidermal cells. These results suggested that 2-MMBI derivatives are promising anti-melanogenic agents.