Molecular Docking, Synthesis, and Tyrosinase Inhibition Activity of Acetophenone Amide: Potential Inhibitor of Melanogenesis

Abstract

Tyrosinase and its related proteins are responsible for pigmentation disorders, and inhibiting tyrosinase is an established strategy to treat hyperpigmentation. The carbonyl scaffolds can be effective inhibitors of tyrosinase activity, and the fact that both benzoic and cinnamic acids are safe natural substances with such a scaffolded structure, it was speculated that hydroxyl-substituted benzoic and cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. These moieties were incorporated into new chemotypes that displayed in vitro inhibitory effect against mushroom tyrosinase with a view to explore antimelanogenic ingredients. The most active compound, 2-((3-acetylphenyl)amino)-2-oxoethyl(E)-3-(2,4-dihydroxyphenyl)acrylate (5c), inhibited mushroom tyrosinase with an IC50 of 0.0020 ± 0.0002 μ M , while 2-((3-acetylphenyl)amino)-2-oxoethyl 2,4-dihydroxybenzoate (3c) had an IC50 of 27.35 ± 3.6 μ M in comparison to the positive control arbutin and kojic acid with a tyrosinase inhibitory activity of IC50 of 191.17 ± 5.5 μ M and IC50 of 16.69 ± 2.8 μ M , respectively. Analysis of enzyme kinetics revealed that 5c is a competitive and reversible inhibitor with dissociation constant (Ki) value 0.0072 μM. In silico docking studies with mushroom tyrosinase (PDB ID 2Y9X) predicted possible binding modes in the enzymatic pocket for these compounds. The orthohydroxyl of the cinnamic acid moiety of 5c is predicted to form hydrogen bond with the active site side chain carbonyl of Asn 260 (2.16 Å) closer to the catalytic site Cu ions. The acetyl carbonyl is picking up another hydrogen bond with Asn 81 (1.90 Å). The inhibitor 5c passed the panassay interference (PAINS) alerts. This study presents the potential of hydroxyl-substituted benzoic and cinnamic acids and could be beneficial for various cosmetic formulations.

Design, Synthesis, and Structural Characterization of Thioflavones and Thioflavonols as Potential Tyrosinase Inhibitors: In Vitro and In Silico Studies

“…The main binding-receptor backbones were histidine, phenylalanine, alanine, and active-site copper ions. The displayed images of docking complexes (Figures10a,b and 11a,b), especially with the interacting image, clarify the formerly concluded data 1,7,14. The surface maps were built over the receptor atoms, leading to a good view of the electrostatic interactions inside the docking complexes.…”

“…The displayed images of docking complexes ( Figures 10 a,b and 11 a,b), especially with the interacting image, clarify the formerly concluded data. 1 , 7 , 14 The surface maps were built over the receptor atoms, leading to a good view of the electrostatic interactions inside the docking complexes. Good inhibition of compounds 2n and 2o exhibit high occupancy of the inside surface grooves pointing to the best blocking of active-site amino acids.…”

“… 13 Moreover, the undesirable phenomena related to melanin have persuaded researchers to search for new potent tyrosinase inhibitors used in skin whitening and antibrowning of foods. 14 …”

“…13 Moreover, the undesirable phenomena related to melanin have persuaded researchers to search for new potent tyrosinase inhibitors used in skin whitening and antibrowning of foods. 14 Moreover, hyperpigmentation is one of the world's most serious health issues. Despite multiple studies on antihyperpigmentation drug synthesis, there is still a high need for the design, synthesis, and discovery of effective antihyperpigmentation medications to address the difficulties associated with existing commercial treatments, such as toxicity and drug resistance.…”

“…Furthermore, tyrosinase inhibitors have become increasingly important in the food industry as well as in the medicinal and cosmetic products due to decreasing the excessive accumulation of pigmentation resulting from the enzyme action. − Over the past decades, many tyrosinase inhibitors have been reported, but only a few possess enough potency and safety in the application of food and pharmaceutical industries . Moreover, the undesirable phenomena related to melanin have persuaded researchers to search for new potent tyrosinase inhibitors used in skin whitening and antibrowning of foods …”