1. Academic Validation
  2. In vitro and in vivo anti-pigmentation effects of 2-mercaptobenzimidazoles as nanomolar tyrosinase inhibitors on mammalian cells and zebrafish embryos: Preparation of pigment-free zebrafish embryos

In vitro and in vivo anti-pigmentation effects of 2-mercaptobenzimidazoles as nanomolar tyrosinase inhibitors on mammalian cells and zebrafish embryos: Preparation of pigment-free zebrafish embryos

  • Eur J Med Chem. 2024 Feb 15:266:116136. doi: 10.1016/j.ejmech.2024.116136.
Dahye Yoon 1 Hee Jin Jung 2 Jieun Lee 1 Hye Jin Kim 1 Hye Soo Park 1 Yu Jung Park 1 Min Kyung Kang 1 Ga Young Kim 1 Dongwan Kang 3 Yujin Park 3 Pusoon Chun 4 Hae Young Chung 2 Hyung Ryong Moon 5
Affiliations

Affiliations

  • 1 Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea.
  • 2 Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea.
  • 3 Department of Medicinal Chemistry, New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
  • 4 College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, 50834, Republic of Korea.
  • 5 Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea. Electronic address: mhr108@pusan.ac.kr.
Abstract

Recently, 10 2-mercaptobenzo[d]imidazole (2-MBI) compounds (1-10) were synthesized. Although all 2-MBI compounds are Tyrosinase inhibitors that inhibit mushroom Tyrosinase at extremely low concentrations (IC50 values: 20-740 nM) and effectively inhibit the browning of apples, to our knowledge, no studies have determined whether 2-MBI compounds inhibit mammalian Tyrosinase. Mammalian Tyrosinase is different from mushroom Tyrosinase in its distribution within the cell and has structural characteristics that are different from mushroom Tyrosinase in amino acid sequence and in the presence of a quaternary structure. Thus, the effect of the 10 2-MBI compounds on mammalian Tyrosinase activity was investigated in B16F10 cells. Six compounds (1-6) exhibited stronger intracellular Tyrosinase inhibition than that of kojic acid and phenylthiourea (PTU), which are known to be the most potent Tyrosinase inhibitors; their strong Tyrosinase inhibitory activity robustly inhibited intracellular melanin production in B16F10 cells. None of the tested 2-MBI compounds exhibited appreciable cytotoxicity in HaCaT and B16F10 cells. To confirm the anti-melanogenic efficacy of the 2-MBI compounds in vivo, a zebrafish embryo model was used. At concentrations 100 times lower than kojic acid, most 2-MBI compounds demonstrated much stronger depigmentation efficacy than that of kojic acid, and three 2-MBI compounds (2-4) showed depigmentation activity similar to or more potent than that of PTU, resulting in nearly pigment-free zebrafish embryos. These results suggest that 2-MBI compounds may be potential therapeutic agents for hyperpigmentation-related disorders.

Keywords

2-MBI; 2-Mercaptobenzimidazole; Anti-melanogenic effect; B16F10 cells; Phenylthiourea; Pigmentation; Tyrosinase; Zebrafish embryo.

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