Novel Amide Derivatives as Potent Tyrosinase Inhibitors; In-vitro, In-vivo Antimelanogenic Activity and Computational Studies

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Author(s): Anser Ali, Zaman Ashraf, Muhammad Rafiq, Ajeet Kumar, Farukh Jabeen, Geon Joon Lee, Fahad Nazir, Mushtaq Ahmed, Myungchull Rhee, Eun Ha Choi*.

Journal Name: Medicinal Chemistry

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Background: Tyrosinase is involved in the melanin biosynthesis and the abnormal accumulation of melanin pigments leading to hyperpigmentation disorders. Controlling the melanogenesis could be an important strategy for treating abnormal pigmentation.

Methods: In the present study, a series of amide derivatives (3a-e and 5a-e) were synthesized aiming to inhibit tyrosinase activity and melanin production. All derivatives were screened for tyrosinase inhibition in a cell-free system. The possible interactions of amide derivatives with tyrosinase enzyme and effect of these interactions on tyrosinase structure were checked by molecular docking in silico and by Circular Dichroism (CD) studies, respectively. The most potent amide derivative (5c) based on cell-free experiments, was further tested for cellular ROS inhibition and for tyrosinase activity using mouse skin melanoma (B16F10) cells.

Results: The tyrosinase inhibitory concentration (IC50) for tested compounds was observed between the range of 68 to 0.0029 μg/ml with a lowest IC50 value of compound 5c which outperforms the reference arbutin and kojic acid. The cellular tyrosinase activity and melanin quantification assay demonstrate that 15μg/ml of 5c attenuates 36% tyrosinase, 24% melanin content of B16F10 cells without significant cell toxicity. Moreover, the zebrafish in vivo assay reveals that 5c effectively reduces melanogenesis without perceptible toxicity. Furthermore, the molecular docking demonstrates that compound 5c interacts with copper ions and multiple amino acids in the active site of tyrosinase with best glide score (-5.387 kcal/mol), essential for mushroom tyrosinase inhibition and the ability to diminish the melanin synthesis in-vitro and in-vivo.

Conclusion: Thus, we propose compound 5c as a potential candidate to control tyrosinase rooted hyperpigmentation in the future.

Keywords: Amide derivatives, tyrosinase, melanin, mouse skin melanoma (B16F10) cells.

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(E-pub Ahead of Print)
DOI: 10.2174/1573406415666190319101329
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