(E)-1-(Furan-2-yl)-(substituted phenyl)prop-2-en-1-one Derivatives as Tyrosinase Inhibitors and Melanogenesis Inhibition: An In Vitro and In Silico Study

Abstract

A series of (E)-1-(furan-2-yl)prop-2-en-1-one derivatives (compounds 1–8) were synthesized and evaluated for their mushroom tyrosinase inhibitory activity. Among these series, compound 8 (2,4-dihydroxy group bearing benzylidene) showed potent tyrosinase inhibitory activity, with respective IC50 values of 0.0433 µM and 0.28 µM for the monophenolase and diphenolase as substrates in comparison to kojic acid as standard compound 19.97 µM and 33.47 µM. Moreover, the enzyme kinetics of compound 8 were determined to be of the mixed inhibition type and inhibition constant (Ki) values of 0.012 µM and 0.165 µM using the Lineweaver-Burk plot. Molecular docking results indicated that compound 8 can bind to the catalytic and allosteric sites 1 and 2 of tyrosinase to inhibit enzyme activity. The computational molecular dynamics analysis further revealed that compound 8 interacted with two residues in the tyrosinase active site pocket, such as ASN260 and MET280. In addition, compound 8 attenuated melanin synthesis and cellular tyrosinase activity, simulated by α-melanocyte-stimulating hormone and 1-methyl-3-isobutylxanthine. Compound 8 also decreased tyrosinase expressions in B16F10 cells. Based on in vitro and computational studies, we propose that compound 8 might be a worthy candidate for the development of an antipigmentation agent.

Identification of (Z)-2-benzylidene-dihydroimidazothiazolone derivatives as tyrosinase inhibitors: Anti-melanogenic effects and in silico studies

“…According to the cumulative docking simulation results, the 2,4-dihydroxyl substituent on the β -phenyl ring contributes to strong binding to tyrosinase through hydrogen bonding at the active site, implying that the 2,4-dihydroxyl substituent plays an important role in tyrosinase inhibition. In some compounds [53] , [58] , [61] , [62] , [64] , [66] , both hydroxyl groups of the 2,4-dihydroxyl substituent participate in hydrogen bonding as hydrogen bond donors, and in some compounds [49] , [60] , [61] , [67] only one of the two hydroxyls participates in hydrogen bonding as a hydrogen bond donor.…”

“…During our studies on this topic over past decades, we have identified a number of benzylidene derivatives with the β-phenyl-α,β-unsaturated carbonyl scaffold more potently inhibit tyrosinase than kojic acid, a representative tyrosinase inhibitor ( Fig. 1 ) [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [29] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] .

Fig.

…”

Silencing of Rab23 by siRNA inhibits ultraviolet B‐induced melanogenesis via downregulation of PKA / CREB / MITF

“…Tyrosinase is a copper‐dependent enzyme that catalyses the conversion of L‐tyrosine to L‐DOPA, which is the rate‐limiting step in melanin biosynthesis 34 . Previous studies have showed that tyrosine metabolism influences the development, differentiation and proliferation of melanocytes, formation and transportation of melanosomes and synthesis of melanin 35 .…”

“…Tyrosinase is a copper-dependent enzyme that catalyses the conversion of L-tyrosine to L-DOPA, which is the rate-limiting step in melanin biosynthesis. 34 Previous studies have showed that tyrosine metabolism influences the development, differentiation and proliferation of melanocytes, formation and transportation of melanosomes and synthesis of melanin. 35 Our results showed that after Rab23 downregulation, the melanin level in B16F10 cells and tyrosinase activity stimulated by UVB were not significantly increased, We analysed the influence of siRab23 on melanogenesis induced by UVB irradiation at the protein level.…”

Novel Anti-Melanogenic Compounds, (Z)-5-(Substituted Benzylidene)-4-thioxothiazolidin-2-one Derivatives: In Vitro and In Silico Insights

“…Several tyrosinase inhibitor scaffolds have been studied over the past few decades, but none of them are used clinically [ 12 , 13 , 14 , 15 ]. During our past studies, we synthesized various derivatives with a phenyl-α,β-unsaturated carbonyl (PUSC) scaffold [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ] with the aim of developing novel, potent tyrosinase inhibitors ( Figure 1 ). In B16F10 melanoma cells, all of these derivatives inhibited tyrosinase and melanogenic activity more potently than kojic acid, a representative tyrosinase inhibitor.…”