title: Analogues of ethionamide, a drug used for multidrug-resistant tuberculosis, exhibit potent inhibition of tyrosinase.
abstract: Tyrosinase catalyzes two distinct sequential reactions in melanin biosynthesis: the hydroxylation of tyrosine to DOPA followed by the oxidation of DOPA to dopaquinone. The central roles of melanin in living species have motivated researchers to maintain constant efforts to discover new agents that modulate tyrosinase activity. In this study, we report on the inhibition of tyrosinase by ethionamide and its analogues. Ethionamide, 2-ethylpyridine-4-carbothioamide, is a second-line antituberculosis drug used for the treatment of multidrug-resistant tuberculosis. The chemical similarity of ethionamide to phenylthiourea, a well-known tyrosinase inhibitor, led us to investigate its inhibitory effects on mushroom tyrosinase and the IC50 was calculated as 4 μM. Five analogues of ethionamide, including another antituberculosis drug, prothionamide, were also inhibitory, with values for IC50 in the range of 3-43 μM. Fluorescence quenching experiments supported a mechanism of direct binding. In contrast, isoniazid, a structural analogue and first-line antituberculosis drug, was a poor inhibitor of tyrosinase. We also tested the effects of ethionamide and its analogues on melanin content in B16F10 cells. At a concentration of 50 μM, the molecules, pyridine-2-carbothioamide and thiobenzamide substantially decreased the melanin content by 44% and 37%, respectively. In addition to identifying other interactions, docking simulations showed that the carbothioamide groups of the molecules make essential contacts with the catalytic di-copper atoms. Our results suggest that carbothioamide can be a central moiety for the development of new and potent tyrosinase inhibitors.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Republic of Korea.
authors.forename: Joonhyeok
authors.initials: J
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea.
authors.forename: Sung-Jean
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Republic of Korea. Electronic address: jjee@knu.ac.kr.
authors.forename: Jun-Goo
authors.initials: JG
authors.lastname: Jee
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005000:Ethionamide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D014442:Monophenol Monooxygenase; D005000:Ethionamide
keywords: Antituberculosis drugs; Carbothioamide compounds; Chemoinformatics; Docking simulation; Ethionamide; Prothionamide; Tyrosinase inhibitors