1. Academic Validation
  2. Identification and molecular mechanism of novel 5-alkenyl-2-benzylaminothiazol-4(5H)-one analogs as anti-melanogenic and antioxidant agents

Identification and molecular mechanism of novel 5-alkenyl-2-benzylaminothiazol-4(5H)-one analogs as anti-melanogenic and antioxidant agents

  • Bioorg Chem. 2023 Nov:140:106763. doi: 10.1016/j.bioorg.2023.106763.
Min Kyung Kang 1 Dahye Yoon 1 Hee Jin Jung 2 Sultan Ullah 3 Jieun Lee 1 Hye Soo Park 1 Hye Jin Kim 1 Dongwan Kang 4 Yujin Park 4 Pusoon Chun 5 Hae Young Chung 2 Hyung Ryong Moon 6
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 Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA.
  • 4 Department of Medicinal Chemistry, New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.
  • 5 College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam 50834, Republic of Korea.
  • 6 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

Mushroom Tyrosinase is a tetramer, whereas mammalian Tyrosinase is a monomeric glycoprotein. In addition, the amino acid sequence of mushroom tyrosinases differs from that of mammalian tyrosinases. MHY2081 exhibits potent inhibitory activity against both mushroom and mammalian tyrosinases. Accordingly, based on the MHY2081 structure, 5-alkenyl-2-benzylaminothiazol-4(5H)-one analogs were designed as a novel anti-tyrosinase agent and synthesized using 2-((3,4-dimethoxybenzyl)amino)thiazol-4(5H)-one (16), a key intermediate obtained via the rearrangement of a benzylamino group. Compounds 6 and 9 (IC50 = 1.5-4.6 µM) exhibited higher mushroom Tyrosinase inhibitory activity than kojic acid (IC50 = 20-21 µM) in the presence of l-tyrosine and/or l-dopa. Based on kinetic analysis using Lineweaver-Burk plots, 6 was a mixed inhibitor, whereas 9 was a competitive inhibitor, and docking simulation results supported that these compounds could bind to the active site of mushroom Tyrosinase. Using B16F10 mammalian cells, we demonstrated that these compounds inhibited melanogenesis more potently than kojic acid, and their anti-melanogenic effects could be attributed to Tyrosinase inhibition. All synthesized compounds could scavenge Reactive Oxygen Species (ROS), with five compounds exhibiting mild-to-strong ABTS+ and DPPH radical-scavenging abilities. Compounds 6 and 9 were potent Tyrosinase inhibitors with strong antioxidant activities against ROS, ABTS+, and DPPH radicals. Moreover, the compounds significantly suppressed Tyrosinase expression in a dose-dependent manner. Collectively, these results suggest that the novel 5-alkenyl-2-benzylaminothiazol-4(5H)-one analogs, especially 6 and 9, are potential anti-melanogenic agents with antioxidant activity.

Keywords

5-Alkenyl-2-benzylaminothiazol-4(5H)-ones; Antioxidant; Docking simulation; Melanin; Tyrosinase.

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