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Highly potent anti-melanogenic effect of 2-thiobenzothiazole derivatives through nanomolar tyrosinase activity inhibition.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2024 Sep; Vol. 150, pp. 107586. Date of Electronic Publication: 2024 Jun 22. - Publication Year :
- 2024
-
Abstract
- Compounds with sulfhydryl substituents and azole compounds exhibit potent anti-tyrosinase potency. 2-Thiobenzothiazole (2-TBT), a hybrid structure of sulfhydryl and azole, exists in two tautomeric forms, with the thione form being predominant according to several studies. 2-TBT derivatives were synthesized as potential tyrosinase inhibitors as the thione tautomeric form has the same N-CS moiety as phenylthiourea (PTU), which is suitable for chelation with the copper ions present in the tyrosinase active site. Eight of the ten 2-TBT derivatives inhibited the monophenolase and diphenolase activities of mushroom tyrosinase, with IC <subscript>50</subscript> values of 0.02-0.83 μM. Kinetic studies and molecular dynamics simulations were performed to determine their mode of action and confirm that the 2-TBT derivatives bind to the tyrosinase active site with high stability. Derivatives 3, 4, 8, and 10 strongly inhibited melanogenesis in B16F10 cells in a pattern similar to the results of cellular tyrosinase inhibition, thereby suggesting that their ability to inhibit melanogenesis was due to their tyrosinase inhibitory activity. In a depigmentation experiment using zebrafish embryos, all 2-TBT derivatives showed better potency than kojic acid, even at 400 to 2000 times lower concentration, and 1 and 10 reduced zebrafish larva pigmentation more strongly than PTU even at 20 times lower concentration. Experiments investigating the changes in tyrosinase inhibitory activity of 2-TBT derivatives in the presence and absence of CuSO <subscript>4</subscript> and their copper chelating ability supported that these derivatives exert their anti-melanogenic effect by chelating the copper ions of tyrosinase. These results suggest that 2-TBT derivatives are promising candidates for the treatment of hyperpigmentation-related disorders.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Mice
Agaricales enzymology
Dose-Response Relationship, Drug
Molecular Structure
Phenylthiourea chemistry
Phenylthiourea pharmacology
Structure-Activity Relationship
Benzothiazoles pharmacology
Benzothiazoles chemistry
Benzothiazoles chemical synthesis
Enzyme Inhibitors pharmacology
Enzyme Inhibitors chemistry
Enzyme Inhibitors chemical synthesis
Melanins antagonists & inhibitors
Melanins metabolism
Monophenol Monooxygenase antagonists & inhibitors
Monophenol Monooxygenase metabolism
Zebrafish
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 150
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38955001
- Full Text :
- https://doi.org/10.1016/j.bioorg.2024.107586