Biochemical and In Silico Studies on Triazole Derivatives as Tyrosinase Inhibitors: Potential Treatment of Hyperpigmentation Related Skin Disorders

• Published in: Medicinal chemistry (Shp-sariqah, United Arab Emirates) Vol. 20; no. 4; p. 397
• Main Authors: Choudhary, Yusra, Atia-Tul-Wahab, Zafar, Humaira, Siddiqui, Salman, Khan, Majid, Khan, Khalid M, Asseri, Amer H, Choudhary, M Iqbal, Atta-Ur-Rahman
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2024
• Subjects: Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hyperpigmentation - drug therapy; Molecular Docking Simulation; Molecular Structure; Monophenol Monooxygenase - antagonists & inhibitors; Monophenol Monooxygenase - metabolism; Pyrones; Skin Diseases - drug therapy; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; melanogenesis; hyperpigmentation; triazole derivatives; Human melanocytes; tyrosinase inhibitors
• ISSN: 1875-6638
• DOI: 10.2174/0115734064271581231219111952

Tyrosinase is a versatile, glycosylated copper-containing oxidase enzyme that mainly catalyzes the biosynthesis of melanin in mammals. Its overexpression leads to the formation of excess melanin, resulting in hyperpigmentary skin disorders, such as dark spots, melasma, freckles, etc. Therefore, inhibition of tyrosinase is a therapeutic approach for the treatment of hyperpigmentation. The current study focused on evaluating tyrosinase inhibitory activities of triazole derivatives 1-20, bearing different substituents on the phenyl ring. 17 derivatives have shown a potent tyrosinase inhibition with IC values between 1.6 to 13 μM, as compared to the standard drug, i.e., kojic acid (IC = 24.1 ± 0.5 μM). Particularly, compounds 11 and 15 displayed 12 times more potent inhibitory effects than the kojic acid. The structure-activity relationship revealed that substituting halogens at the C-4 position of the benzene ring renders remarkable anti-tyrosinase activities. Compounds 1-3 and 8 showed a competitive type of inhibition, while compounds 5, 11, and 15 showed a non-competitive mode of inhibition. Next, we performed molecular docking analyses to study the binding modes and interactions between the ligands (inhibitors) and the active site of the tyrosinase enzyme (receptor). Besides this, we have assessed the toxicity profile of inhibitors on the BJ human fibroblast cell line. The majority of the newly identified tyrosinase inhibitors were found to be noncytotoxic. The results presented herein form the basis of further studies on triazole derivatives as potential drug leads against tyrosinase-related diseases.