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Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies.
Drug Des Devel Ther. 2017; 11:2029-2046.DD

Abstract

The present work describes the synthesis of few hydroxylated amide derivatives as melanogenesis inhibitors. In vitro, in vivo and computational studies proved that compound 6d is a highly potent melanogenesis inhibitor compared to standard kojic acid. The title amides 4a-e and 6a-e were synthesized following simple reaction routes with excellent yields. Most of the synthesized compounds exhibited good mushroom tyrosinase inhibitory activity, but compound 6d showed excellent activity (IC50 0.15 µM) compared to standard kojic acid (IC50 16.69 µM). Lineweaver-Burk plots were used for the determination of kinetic mechanism, and it was found that compounds 4c and 6d showed non-competitive inhibition while 6a and 6b showed mixed-type inhibition. The kinetic mechanism further revealed that compound 6d formed irreversible complex with the target enzyme tyrosinase. The Ki values determined for compounds 4c, 6a, 6b and 6d are 0.188, 0.84, 2.20 and 0.217 µM respectively. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound 6d exhibited 91.9% inhibi-tory activity at a concentration of 50 µg/mL. In vivo cytotoxicity evaluation of compound 6d in zebrafish embryos showed that it is non-toxic to zebrafish. Melanin depigmentation assay performed in zebrafish indicated that compound 6d possessed greater potential in decreasing melanin contents compared to kojic acid at the same concentration. Computational studies also supported the wet lab findings as compound 6d showed a highest binding affinity with the target protein (PDBID: 2Y9X) with a binding energy value of -7.90 kcal/mol. Molecular dynamic simulation studies also proved that amide 6d formed the most stable complex with tyrosinase. Based upon our in vitro, in vivo and computational studies, we propose that compound 6d is a promising candidate for the development of safe cosmetic agent.

Authors+Show Affiliations

Department of Biology, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea.Department of Chemistry, Allama Iqbal Open University, Islamabad.Department of Biology, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea.Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunawwarah, Kingdom of Saudi Arabia.Faculty of Pharmacy, Bahauddin Zakria University, Multan, Pakistan.Department of Biology, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28740364

Citation

Abbas, Qamar, et al. "Development of Highly Potent Melanogenesis Inhibitor By in Vitro, in Vivo and Computational Studies." Drug Design, Development and Therapy, vol. 11, 2017, pp. 2029-2046.
Abbas Q, Ashraf Z, Hassan M, et al. Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies. Drug Des Devel Ther. 2017;11:2029-2046.
Abbas, Q., Ashraf, Z., Hassan, M., Nadeem, H., Latif, M., Afzal, S., & Seo, S. Y. (2017). Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies. Drug Design, Development and Therapy, 11, 2029-2046. https://doi.org/10.2147/DDDT.S137550
Abbas Q, et al. Development of Highly Potent Melanogenesis Inhibitor By in Vitro, in Vivo and Computational Studies. Drug Des Devel Ther. 2017;11:2029-2046. PubMed PMID: 28740364.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies. AU - Abbas,Qamar, AU - Ashraf,Zaman, AU - Hassan,Mubashir, AU - Nadeem,Humaira, AU - Latif,Muhammad, AU - Afzal,Samina, AU - Seo,Sung-Yum, Y1 - 2017/07/05/ PY - 2017/7/26/entrez PY - 2017/7/26/pubmed PY - 2018/6/15/medline KW - computational studies KW - melanin quantification KW - melanogenesis KW - tyrosinase inhibition KW - zebrafish SP - 2029 EP - 2046 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 11 N2 - The present work describes the synthesis of few hydroxylated amide derivatives as melanogenesis inhibitors. In vitro, in vivo and computational studies proved that compound 6d is a highly potent melanogenesis inhibitor compared to standard kojic acid. The title amides 4a-e and 6a-e were synthesized following simple reaction routes with excellent yields. Most of the synthesized compounds exhibited good mushroom tyrosinase inhibitory activity, but compound 6d showed excellent activity (IC50 0.15 µM) compared to standard kojic acid (IC50 16.69 µM). Lineweaver-Burk plots were used for the determination of kinetic mechanism, and it was found that compounds 4c and 6d showed non-competitive inhibition while 6a and 6b showed mixed-type inhibition. The kinetic mechanism further revealed that compound 6d formed irreversible complex with the target enzyme tyrosinase. The Ki values determined for compounds 4c, 6a, 6b and 6d are 0.188, 0.84, 2.20 and 0.217 µM respectively. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound 6d exhibited 91.9% inhibi-tory activity at a concentration of 50 µg/mL. In vivo cytotoxicity evaluation of compound 6d in zebrafish embryos showed that it is non-toxic to zebrafish. Melanin depigmentation assay performed in zebrafish indicated that compound 6d possessed greater potential in decreasing melanin contents compared to kojic acid at the same concentration. Computational studies also supported the wet lab findings as compound 6d showed a highest binding affinity with the target protein (PDBID: 2Y9X) with a binding energy value of -7.90 kcal/mol. Molecular dynamic simulation studies also proved that amide 6d formed the most stable complex with tyrosinase. Based upon our in vitro, in vivo and computational studies, we propose that compound 6d is a promising candidate for the development of safe cosmetic agent. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/28740364/Development_of_highly_potent_melanogenesis_inhibitor_by_in_vitro_in_vivo_and_computational_studies_ L2 - https://dx.doi.org/10.2147/DDDT.S137550 DB - PRIME DP - Unbound Medicine ER -