Cargando…
Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies
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...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503496/ https://www.ncbi.nlm.nih.gov/pubmed/28740364 http://dx.doi.org/10.2147/DDDT.S137550 |
_version_ | 1783249108781236224 |
---|---|
author | Abbas, Qamar Ashraf, Zaman Hassan, Mubashir Nadeem, Humaira Latif, Muhammad Afzal, Samina Seo, Sung-Yum |
author_facet | Abbas, Qamar Ashraf, Zaman Hassan, Mubashir Nadeem, Humaira Latif, Muhammad Afzal, Samina Seo, Sung-Yum |
author_sort | Abbas, Qamar |
collection | PubMed |
description | 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 (IC(50) 0.15 µM) compared to standard kojic acid (IC(50) 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. |
format | Online Article Text |
id | pubmed-5503496 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-55034962017-07-24 Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies Abbas, Qamar Ashraf, Zaman Hassan, Mubashir Nadeem, Humaira Latif, Muhammad Afzal, Samina Seo, Sung-Yum Drug Des Devel Ther Original Research 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 (IC(50) 0.15 µM) compared to standard kojic acid (IC(50) 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. Dove Medical Press 2017-07-05 /pmc/articles/PMC5503496/ /pubmed/28740364 http://dx.doi.org/10.2147/DDDT.S137550 Text en © 2017 Abbas et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Abbas, Qamar Ashraf, Zaman Hassan, Mubashir Nadeem, Humaira Latif, Muhammad Afzal, Samina Seo, Sung-Yum Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies |
title | Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies |
title_full | Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies |
title_fullStr | Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies |
title_full_unstemmed | Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies |
title_short | Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies |
title_sort | development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503496/ https://www.ncbi.nlm.nih.gov/pubmed/28740364 http://dx.doi.org/10.2147/DDDT.S137550 |
work_keys_str_mv | AT abbasqamar developmentofhighlypotentmelanogenesisinhibitorbyinvitroinvivoandcomputationalstudies AT ashrafzaman developmentofhighlypotentmelanogenesisinhibitorbyinvitroinvivoandcomputationalstudies AT hassanmubashir developmentofhighlypotentmelanogenesisinhibitorbyinvitroinvivoandcomputationalstudies AT nadeemhumaira developmentofhighlypotentmelanogenesisinhibitorbyinvitroinvivoandcomputationalstudies AT latifmuhammad developmentofhighlypotentmelanogenesisinhibitorbyinvitroinvivoandcomputationalstudies AT afzalsamina developmentofhighlypotentmelanogenesisinhibitorbyinvitroinvivoandcomputationalstudies AT seosungyum developmentofhighlypotentmelanogenesisinhibitorbyinvitroinvivoandcomputationalstudies |