Design, Synthesis and Biological Evaluation of Oxindole-Based Chalcones as Small-Molecule Inhibitors of Melanogenic Tyrosinase

Abstract

The enzyme tyrosinase regulates melanogenesis and skin hyperpigmentation by converting L-3,4-dihydroxyphenylalanine (L-DOPA) into dopaquinone, a key step in the melanin biosynthesis. The present work deals with design and synthesis of various oxindole-based chalcones as monophenolase and diphenolase activity inhibitors of tyrosinase. Among the screened compounds, 4-hydroxy-3-methoxybenzylidene moiety bearing chalcone (7) prepared by one pot reaction of oxindole and vanillin displayed the highest activity against tyrosinase with IC 50 s of 63.37 and 59.71 µM in monophenolase and diphenolase activity assays, respectively. In molecular docking studies, chalcone 7 also showed the highest binding affinity towards the enzyme tyrosinase while exhibiting the lowest estimated free energy of binding, among all the ligands docked.Key words tyrosinase inhibitor; oxindole-based chalcone; melanogenesis; molecular docking Tyrosinase is a major enzyme of melanogenic cascade, accountable for hydroxylation of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) and subsequent oxidation of L-DOPA to dopaquinone, the significant steps in melanin production.

A comprehensive review on tyrosinase inhibitors

“…Also, tyrosinase inhibitory effects of several synthetic chalcones and their derivatives were evaluated by various researchers. Oxindole-based chalcones 294 , 1-(2-cyclohexylmethoxy-6-hydroxy-phenyl)-3-(4-hydroxymethyl-phenyl) propenone derivative 295 , isoxazole chalcone derivatives 296 , some azachalcones and their oximes 297 , 298 , 2,4,2',4'-tetrahydroxychalcone and its two derivatives (1,3,5-tris-(2,4-dihydroxy-phenyl) pentane-1,5-dione and 7,2',4'-trihydroxyflavanone) 299 , 2',4',6'-trihydroxychalcones 300 , naphthyl chalcones 301 and chalcone thiosemicarbazide derivatives 302 have been identified as a new class of tyrosinase inhibitors. Interestingly, the most important factors in the efficacy of a chalcone are the location of the hydroxyl groups on both aromatic rings and the number of these hydroxyls and the presence of a catechol moiety don't correlate with increasing tyrosinase inhibition potency 303 .…”

“…Additionally, further improvements of in vitro detection methods for rapidly screening tyrosinase inhibitors may be achieved through using virtual screening 30 and construction of quantitative structure–activity relationship (QSAR) models of inhibitors 31 , 32 . Thus, a combination of bioinformatics simulation and biological in vitro analysis will be useful to understand the functional mechanisms of the tested compounds 9 , 21 , 27 , 33–48 . Lately, Gao et al.…”

Natural and Bioinspired Phenolic Compounds as Tyrosinase Inhibitors for the Treatment of Skin Hyperpigmentation: Recent Advances

“…Quite low IC50 values have been reported also for dihydrolipoic acid conjugates of caffeic acid and its methylester [136,137], as well as for thiochromanone compounds [138], diamides [139], or esters [140,141] related to p-coumaric acid. Similar scaffolds are chalcones [142][143][144][145][146][147][148][149][150][151][152][153][154][155][156], characterized by an enone moiety linked to a phenyl ring as well. Particularly active as mushroom tyrosinase inhibitors are 2,2′,4,4′-tetrahydroxychalcone (IC50 = 0.08 μM) and its derivatives [149], followed by azachalcones (IC50 = 1.70-2.30 μM) [150], chalcone oximes (IC50 = 4.5-8 μM) [151], and a chalcone based pyrazoline (IC50 = 4.72 μM) [152] ( Figure 18).…”

Design, Synthesis, in Vitro, and in Silico Evaluation of N‐Phenylacetamide‐Oxindole‐Thiosemicarbazide Hybrids as New Potential Tyrosinase Inhibitors

“…[14][15][16] Based on the recent evidence, oxindole-based chalcone deriva-tives displayed anti-TYR activity. [17] For example, oxindole derivative A showed good TYR inhibitory activity (IC 50 = 63.37 μM) compared to Kojic acid (IC 50 = 22.52 μM). On the other hand, several series of N-phenylacetamide derivatives with high inhibitory activity against TYR have been reported.…”

“…In continues of our efforts to development of new synthetic TYR inhibitor candidates, we have introduced a new series of compounds as TYR inhibitors 7 by considering three potent TYR inhibitors A – C and combining their effective pharmacophore units based on molecular hybridization ( Figure 2). [14–16] Based on the recent evidence, oxindole‐based chalcone derivatives displayed anti‐TYR activity [17] . For example, oxindole derivative A showed good TYR inhibitory activity (IC 50 =63.37 μM) compared to Kojic acid (IC 50 =22.52 μM).…”