Resorcinol-based hemiindigoid derivatives as human tyrosinase inhibitors and melanogenesis suppressors in human melanoma cells

• Published in: European journal of medicinal chemistry Vol. 246; pp. 114972 - 114988
• Main Authors: Roulier, Brayan, Rush, Inbal, Lazinski, Leticia M., Pérès, Basile, Olleik, Hamza, Royal, Guy, Fishman, Ayelet, Maresca, Marc, Haudecoeur, Romain
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.01.2023; Elsevier
• Subjects: Aurone; Chemistry, Medicinal; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hemiindigoid; human Tyrosinase; Humans; Indanone; Life Sciences; Life Sciences & Biomedicine; Melanins; Melanogenesis; Melanoma; Melanoma - drug therapy; Molecular Docking Simulation; Monophenol Monooxygenase; Pharmacology & Pharmacy; Resorcinols - pharmacology; Science & Technology; Indanone; Aurone; Hemiindigoid; Melanogenesis; human Tyrosinase; Melanoma; OXIDATION; AURONES; ACTIVE-SITE; DISCOVERY; MEDICINAL CHEMISTRY; MUSHROOM; DISEASE
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114972

Human tyrosinase (hsTYR) catalyzes the key steps of melanogenesis, making it a privileged target for reducing melanin production in vivo. However, very few hsTYR inhibitors have been reported so far in the literature, whereas thousands of mushroom tyrosinase (abTYR) inhibitors are known. Yet, as these enzymes are actually very different, including at their active sites, there is an urgent need for new true hsTYR inhibitors in order to enable human-directed pharmacological and dermocosmetic applications without encountering the inefficiency and toxicity issues currently triggered by kojic acid or hydroquinone. Starting from the two most active compounds reported to date, i.e. a 2-hydroxypyridine-embedded aurone and thiamidol, we combined herein key structural elements and developed new nanomolar hsTYR inhibitors with cell-based activity. From a complete series of thirty-eight synthesized derivatives, excellent inhibition values were obtained for two compounds in both human melanoma cell lysates and purified hsTYR assays, and a promising improvement was observed in whole cell experiments. [Display omitted] •Thirty-eight resorcinol compounds are screened against melanoma cell lysates.•Two hemiindigoids are identified as nanomolar inhibitors of human tyrosinase.•The proposed binding mode is reminiscent of those of natural substrate l-tyrosine.•An improvement of cellular activity is recorded compared to the parent compound.