Design, Synthesis, and Biological Evaluation of Novel Hybrids Containing Dihydrochalcone as Tyrosinase Inhibitors to Treat Skin Hyperpigmentation

Xue, Songtao; Li, Zhiwei; Ze, Xiaotong; Wu, Xiuyuan; He, Chen; Shuai, Wen; Marlow, Maria; Chen, Jian; Scurr, David; Zhu, Zheying; Xu, Jinyi; Xu, Shengtao

Abstract

Excessive melanin deposition may lead to a series of skin disorders. The production of melanin is carried out by melanocytes, in which the enzyme tyrosinase performs a key role. In this work, we identified a series of novel tyrosinase inhibitor hybrids with a dihydrochalcone skeleton and resorcinol structure, which can inhibit tyrosinase activity and reduce the melanin content in the skin. Compound 11c possessed the most potent activity against tyrosinase, showing IC50 values at nanomolar concentration ranges, along with significant antioxidant activity and low cytotoxicity. Furthermore, in vitro permeation tests, supported by HPLC analysis and 3D OrbiSIMS imaging visualization, revealed the excellent permeation of 11c. More importantly, compound 11c reduced the melanin content on UV-induced skin pigmentation in a guinea pig model in vivo. These results suggest that compound 11c may serve as a promising potent tyrosinase inhibitor for the development of a potential therapy to treat skin hyperpigmentation.

Citation

Xue, S., Li, Z., Ze, X., Wu, X., He, C., Shuai, W., …Xu, S. (2023). Design, Synthesis, and Biological Evaluation of Novel Hybrids Containing Dihydrochalcone as Tyrosinase Inhibitors to Treat Skin Hyperpigmentation. Journal of Medicinal Chemistry, 66(7), 5099–5117. https://doi.org/10.1021/acs.jmedchem.3c00012

• Journal Article Type: Article
• Acceptance Date: Mar 9, 2023
• Online Publication Date: Mar 20, 2023
• Publication Date: Mar 20, 2023
• Deposit Date: Mar 21, 2023
• Publicly Available Date: Mar 21, 2024
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society (ACS)
• Peer Reviewed: Peer Reviewed
• Volume: 66
• Issue: 7
• Pages: 5099–5117
• DOI: https://doi.org/10.1021/acs.jmedchem.3c00012
• Keywords: Anatomy, Inhibition, Inhibitors, Ions, Peptides and proteins
• Public URL: https://nottingham-repository.worktribe.com/output/18808553
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00012
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Journal of Medicinal Chemistry after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00012.