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In silico and in vitro insights into tyrosinase inhibitors with a 2-thioxooxazoline-4-one template.

ABSTRACT: The ?-phenyl-?,?-unsaturated carbonyl (PUSC) scaffold confers tyrosinase inhibitory activity, and in the present study, 16 (Z)-5-(substituted benzylidene)-3-phenyl-2-thioxooxazolidin-4-one analogues containing this scaffold were synthesized. Mushroom tyrosinase inhibitory activities were examined. Compound 1c (IC₅₀ = 4.70 ± 0.40 ?M) and compound 1j (IC₅₀ = 11.18 ± 0.54 ?M) inhibited tyrosinase by 4.9 and 2.1-fold, respectively, and did so more potently than kojic acid (IC₅₀ = 23.18 ± 0.11 ?M). Kinetic analysis of tyrosinase inhibition revealed that 1c and 1j inhibited tyrosinase competitively. Results of docking simulation with mushroom tyrosinase using four docking programs suggested that 1c and 1j bind more strongly than kojic acid to the active site of tyrosinase and supported kinetic findings that both compounds are competitive inhibitors. The docking results of human tyrosinase homology model indicated that 1c and 1j can also strongly inhibit human tyrosinase. EZ-cytox assays revealed 1c and 1j were not cytotoxic to B16F10 melanoma cells. The effects of 1c and 1j on cellular tyrosinase activity and melanin production were also investigated in ?-MSH- and IBMX-co-stimulated these cells. Both compounds significantly and dose-dependently reduced tyrosinase activity, and at 10 µM were more potent than kojic acid at 20 µM. Compounds 1c and 1j also inhibited melanogenesis, which suggested that the inhibitory effects of these compounds on melanin production were mainly attributable to their inhibitions of tyrosinase. These results indicate that compounds 1c and 1j with the PUSC scaffold have potential use as whitening agents for the treatment of hyperpigmentation-associated diseases.

SUBMITTER: Choi I

PROVIDER: S-EPMC7753086 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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In silico and in vitro insights into tyrosinase inhibitors with a 2-thioxooxazoline-4-one template.

Choi Inkyu I Park Yujin Y Ryu Il Young IY Jung Hee Jin HJ Ullah Sultan S Choi Heejeong H Park Chaeun C Kang Dongwan D Lee Sanggwon S Chun Pusoon P Young Chung Hae H Moon Hyung Ryong HR

Computational and structural biotechnology journal 20201211

The β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold confers tyrosinase inhibitory activity, and in the present study, 16 (Z)-5-(substituted benzylidene)-3-phenyl-2-thioxooxazolidin-4-one analogues containing this scaffold were synthesized. Mushroom tyrosinase inhibitory activities were examined. Compound 1c (IC50 = 4.70 ± 0.40 μM) and compound 1j (IC50 = 11.18 ± 0.54 μM) inhibited tyrosinase by 4.9 and 2.1-fold, respectively, and did so more potently ...[more]

PMID: 33363708

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Project description:To find new potential tyrosinase inhibitors, a diverse range of 2-arylchromone-4-thione derivatives (2a-2p) were designed and synthesized by employing a multistep strategy, and the newly synthesized compounds, for the first time, were screened in vitro for their tyrosinase inhibitory activity. In this context, the newly synthesized compounds (2a-2p) were characterized using a combination of several spectroscopic techniques including Fourier transform infrared, UV-vis, 1H NMR, and 13C NMR spectroscopies and electron ionization-mass spectrometry. All the target compounds were potent against tyrosinase as compared to the standard inhibitor kojic acid (half-maximal inhibitory concentration (IC50) = 12.6 ± 0.6 μM). The compounds (2a-2p) produced IC50 values in the range from 1.12 ± 0.04 to 5.68 ± 0.13 μM. Among the synthesized 4-thioflavones and 4-thioflavonols, the compound 2n exhibited excellent tyrosinase inhibitory activity with the lowest IC50 of 1.12 ± 0.04 μM that could be recommended as potential lead candidates to cure tyrosinase-mediated hyperpigmentation in the future. A kinetic study of compound 2n revealed that compound 2n inhibited tyrosinase in a competitive mode. Furthermore, the nontoxic performance of the most beneficial compounds ranging from 1 to 25 g/mL was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test method for A375 human melanoma cells for the highly efficient target compounds (2m, 2n, 2o, and 2p). Moreover, a molecular modeling study was performed against tyrosinase enzyme (2Y9X) to check the binding interactions of the synthesized compounds (2a-2p) against the target protein. Furthermore, quantitative structure-activity relationship studies were conducted based on an antityrosinase assay. The value of the correlation coefficient (R 2) 0.9997 shows that there was a good correlation between (2a-2p) structures and selected properties. The geometry optimization of all complexes was performed by using Gaussian 09. Additionally, a drug-likeness research was used to establish the potent analogues' positive action as a new antityrosinase agent (2n, 2o, and 2p).

Dataset Information

In silico and in vitro insights into tyrosinase inhibitors with a 2-thioxooxazoline-4-one template.

Publications

<i>In silico</i> and <i>in vitro</i> insights into tyrosinase inhibitors with a 2-thioxooxazoline-4-one template.

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