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Novel Amide Derivatives as Potent Tyrosinase Inhibitors; In-vitro, In-vivo Antimelanogenic Activity and Computational Studies.
Med Chem. 2019; 15(7):715-728.MC

Abstract

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.

Authors+Show Affiliations

Department of Zoology, Mirpur University of Science and Technology (MUST), Mirpur-10250 (AJK), Pakistan. Plasma Bioscience Research Center, Kwangwoon University, 20 Kwangwoon-gil, Nowon-gu, Seoul 139-701, South Korea.Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan.Department of Physiology and Biochemistry, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Punjab, Pakistan.Department of Biological Sciences, Chungnam National University, Daejeon 305-764, Korea.Department of Biology, Laurentian University, 935 Ramsey Lake Road, Sudbury, P3E 2C6, ON, Canada.Plasma Bioscience Research Center, Kwangwoon University, 20 Kwangwoon-gil, Nowon-gu, Seoul 139-701, South Korea.Department of Entomology, Faculty of Crop Protection, Sindh Agriculture University, Tandojam, Pakistan.Department of Zoology, Mirpur University of Science and Technology (MUST), Mirpur-10250 (AJK), Pakistan.Department of Biological Sciences, Chungnam National University, Daejeon 305-764, Korea.Plasma Bioscience Research Center, Kwangwoon University, 20 Kwangwoon-gil, Nowon-gu, Seoul 139-701, South Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30892163

Citation

Ali, Anser, et al. "Novel Amide Derivatives as Potent Tyrosinase Inhibitors; In-vitro, In-vivo Antimelanogenic Activity and Computational Studies." Medicinal Chemistry (Shariqah (United Arab Emirates)), vol. 15, no. 7, 2019, pp. 715-728.
Ali A, Ashraf Z, Rafiq M, et al. Novel Amide Derivatives as Potent Tyrosinase Inhibitors; In-vitro, In-vivo Antimelanogenic Activity and Computational Studies. Med Chem. 2019;15(7):715-728.
Ali, A., Ashraf, Z., Rafiq, M., Kumar, A., Jabeen, F., Lee, G. J., Nazir, F., Ahmed, M., Rhee, M., & Choi, E. H. (2019). Novel Amide Derivatives as Potent Tyrosinase Inhibitors; In-vitro, In-vivo Antimelanogenic Activity and Computational Studies. Medicinal Chemistry (Shariqah (United Arab Emirates)), 15(7), 715-728. https://doi.org/10.2174/1573406415666190319101329
Ali A, et al. Novel Amide Derivatives as Potent Tyrosinase Inhibitors; In-vitro, In-vivo Antimelanogenic Activity and Computational Studies. Med Chem. 2019;15(7):715-728. PubMed PMID: 30892163.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel Amide Derivatives as Potent Tyrosinase Inhibitors; In-vitro, In-vivo Antimelanogenic Activity and Computational Studies. AU - Ali,Anser, AU - Ashraf,Zaman, AU - Rafiq,Muhammad, AU - Kumar,Ajeet, AU - Jabeen,Farukh, AU - Lee,Goon Joon, AU - Nazir,Fahad, AU - Ahmed,Mushtaq, AU - Rhee,Myungchull, AU - Choi,Eun Ha, PY - 2018/06/08/received PY - 2018/12/01/revised PY - 2019/03/03/accepted PY - 2019/3/21/pubmed PY - 2019/3/21/medline PY - 2019/3/21/entrez KW - Amide derivatives KW - amino acids KW - antimelanogenic activity KW - melanin KW - mouse skin melanoma (B16F10) cells KW - tyrosinase. SP - 715 EP - 728 JF - Medicinal chemistry (Shariqah (United Arab Emirates)) JO - Med Chem VL - 15 IS - 7 N2 - 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. SN - 1875-6638 UR - https://www.unboundmedicine.com/medline/citation/30892163/Novel_Amide_Derivatives_as_Potent_Tyrosinase_Inhibitors L2 - http://www.eurekaselect.com/170819/article DB - PRIME DP - Unbound Medicine ER -