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: Joonhyeok Choi, Sung-Jean Park, Jun-Goo Jee
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 106 Pg. 157-66 (Dec 01 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 26544630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antitubercular Agents
• Enzyme Inhibitors
• Monophenol Monooxygenase
• Ethionamide

Topics

• Animals
• Antitubercular Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Ethionamide (chemical synthesis, chemistry, pharmacology)
• Mice
• Microbial Sensitivity Tests
• Molecular Structure
• Monophenol Monooxygenase (antagonists & inhibitors, metabolism)
• Mycobacterium tuberculosis (drug effects, metabolism)
• Structure-Activity Relationship
• Tuberculosis, Multidrug-Resistant (drug therapy, metabolism)