Inhibitory effects of N-(acryloyl)benzamide derivatives on tyrosinase and melanogenesis

• Published in: Bioorganic & medicinal chemistry 2019-09, Vol.27 (17), p.3929-3937
• Main Authors: Lee, Sanggwon, Ullah, Sultan, Park, Chaeun, Won Lee, Hee, Kang, Dongwan, Yang, Jungho, Akter, Jinia, Park, Yujin, Chun, Pusoon, Moon, Hyung Ryong
• Format: Article
• Language: English
• Subjects: (N-(acryloyl)benzamide) derivatives; B16F10 melanoma cells; Horner-Wadsworth-Emmons olefination; Inhibitor; Melanogenesis; Tyrosinase
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.07.034

[Display omitted] •Ten NAB derivatives were synthesized via Horner-Wadsworth-Emmons olefination.•1a and 1j exhibited potent anti-melanogenic effects compared to kojic acid.•1a and 1j showed stronger binding affinities for tyrosinase than kojic acid. Targeting of tyrosinase has proven to be the best means of identifying safe, efficacious, and potent tyrosinase inhibitors for whitening skin. We designed and synthesized ten NAB (N-(acryloyl)benzamide) derivatives (1a–1j) using the Horner-Wadsworth-Emmons olefination of diethyl (2-benzamido-2-oxoethyl)phosphonate and appropriate benzaldehydes. A mushroom tyrosinase inhibitory assay showed compounds 1a (36.71 ± 2.14% inhibition) and 1j (25.99 ± 2.77% inhibition) inhibited tyrosinase more than the other eight NAB derivatives and kojic acid (21.56 ± 2.93% inhibition), and docking studies indicated 1a (−6.9 kcal/mole) and 1j (−7.5 kcal/mole) had stronger binding affinities for tyrosinase than kojic acid (−5.7 kcal/mole). At a concentration of 25 μM, 1a and 1j were nontoxic in B16F10 melanoma cells and exhibited stronger tyrosinase inhibition (59.70% and 76.77%, respectively) than kojic acid (50.30% inhibition) or arbutin (41.78% inhibition at 400 μM). Similarly, in B16F10 melanoma cells, compounds 1a and 1j at 25 μM decreased total melanin content by 47.97% and 61.77%, respectively (kojic acid; 38.98%). Similarities between inhibitions of tyrosinase activity and melanin contents suggested the anti-melanogenic effects of 1a and 1j were due to tyrosinase inhibition. The excellent DPPH scavenging activity of 1j suggests it might enhance in vivo effect on melanin contents. The study suggests compound 1j offers a potential starting point for the development of safe, potent tyrosinase inhibitors.