Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitors
Abstract A novel series of kojic acid fused 2-amino-3-cyano-4H-pyran derivatives were synthesized via a multicomponent reaction involving kojic acid, benzyloxy benzaldehyde, and malonitrile as tyrosinase inhibitors. Subsequently, the structures of the compounds were characterized using FT-IR, 1H-, a...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | BMC Chemistry |
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| Online Access: | https://doi.org/10.1186/s13065-024-01134-1 |
| _version_ | 1797275971100868608 |
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| author | Zahra Najafi Maryam Zandi Haramabadi Gholamabbas Chehardoli Ahmad Ebadi Aida Iraji |
| author_facet | Zahra Najafi Maryam Zandi Haramabadi Gholamabbas Chehardoli Ahmad Ebadi Aida Iraji |
| author_sort | Zahra Najafi |
| collection | DOAJ |
| description | Abstract A novel series of kojic acid fused 2-amino-3-cyano-4H-pyran derivatives were synthesized via a multicomponent reaction involving kojic acid, benzyloxy benzaldehyde, and malonitrile as tyrosinase inhibitors. Subsequently, the structures of the compounds were characterized using FT-IR, 1H-, and 13C-NMR spectroscopic analyses. The designed compounds fall into three series: (1) 4-benzyloxy-phenyl kojopyran 6a–e, (2) 3-benzyloxy- phenyl kojopyran derivatives 6f–j, and (3) 4-benzyloxy-3-methoxy-phenyl kojopyran derivative 6 k–o. The assessment of tyrosinase inhibition activity was conducted using L-Dopa as the substrate. Among synthesized compounds, 2-amino-4-(4-((4-fluorobenzyl)oxy)phenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6b) demonstrated the highest antityrosinase activity with a competitive inhibition pattern (IC50 = 7.69 ± 1.99 μM) as compared to the control agent kojic acid (IC50 = 23.64 ± 2.56 µM). Since compound 6b was synthesized as a racemic mixture, in silico studies were performed for both R and S enantiomers. The R- enantiomer showed critical interactions compared with the S-enantiomer. Specifically, it established hydrogen bonds and hydrophobic interactions with crucial and highly conserved amino acids within the enzyme's binding site in the target protein. Moreover, the molecular dynamics simulations revealed that compound 6b demonstrated significant interactions with essential residues of the binding site, resulting in a stable complex throughout the entire simulation run. The drug-like and ADMET properties predictions showed an acceptable profile for compound 6b. Thus, it can serve as a drug candidate to develop more potent antityrosinase agents due to its low toxicity and its high inhibition activity. |
| first_indexed | 2024-03-07T15:21:40Z |
| format | Article |
| id | doaj.art-33015a7db20c4ca1aef5af965c2aa023 |
| institution | Directory Open Access Journal |
| issn | 2661-801X |
| language | English |
| last_indexed | 2024-03-07T15:21:40Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Chemistry |
| spelling | doaj.art-33015a7db20c4ca1aef5af965c2aa0232024-03-05T17:34:53ZengBMCBMC Chemistry2661-801X2024-02-0118111610.1186/s13065-024-01134-1Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitorsZahra Najafi0Maryam Zandi Haramabadi1Gholamabbas Chehardoli2Ahmad Ebadi3Aida Iraji4Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical SciencesDepartment of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical SciencesDepartment of Medicinal Chemistry, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical SciencesDepartment of Medicinal Chemistry, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical SciencesStem Cells Technology Research Center, Shiraz University of Medical SciencesAbstract A novel series of kojic acid fused 2-amino-3-cyano-4H-pyran derivatives were synthesized via a multicomponent reaction involving kojic acid, benzyloxy benzaldehyde, and malonitrile as tyrosinase inhibitors. Subsequently, the structures of the compounds were characterized using FT-IR, 1H-, and 13C-NMR spectroscopic analyses. The designed compounds fall into three series: (1) 4-benzyloxy-phenyl kojopyran 6a–e, (2) 3-benzyloxy- phenyl kojopyran derivatives 6f–j, and (3) 4-benzyloxy-3-methoxy-phenyl kojopyran derivative 6 k–o. The assessment of tyrosinase inhibition activity was conducted using L-Dopa as the substrate. Among synthesized compounds, 2-amino-4-(4-((4-fluorobenzyl)oxy)phenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6b) demonstrated the highest antityrosinase activity with a competitive inhibition pattern (IC50 = 7.69 ± 1.99 μM) as compared to the control agent kojic acid (IC50 = 23.64 ± 2.56 µM). Since compound 6b was synthesized as a racemic mixture, in silico studies were performed for both R and S enantiomers. The R- enantiomer showed critical interactions compared with the S-enantiomer. Specifically, it established hydrogen bonds and hydrophobic interactions with crucial and highly conserved amino acids within the enzyme's binding site in the target protein. Moreover, the molecular dynamics simulations revealed that compound 6b demonstrated significant interactions with essential residues of the binding site, resulting in a stable complex throughout the entire simulation run. The drug-like and ADMET properties predictions showed an acceptable profile for compound 6b. Thus, it can serve as a drug candidate to develop more potent antityrosinase agents due to its low toxicity and its high inhibition activity.https://doi.org/10.1186/s13065-024-01134-1Kojic acidBenzyloxy benzylidene2-Amino-3-cyano-4H-pyranMolecular dynamics simulationTyrosinase inhibitors |
| spellingShingle | Zahra Najafi Maryam Zandi Haramabadi Gholamabbas Chehardoli Ahmad Ebadi Aida Iraji Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitors BMC Chemistry Kojic acid Benzyloxy benzylidene 2-Amino-3-cyano-4H-pyran Molecular dynamics simulation Tyrosinase inhibitors |
| title | Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitors |
| title_full | Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitors |
| title_fullStr | Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitors |
| title_full_unstemmed | Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitors |
| title_short | Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitors |
| title_sort | design synthesis and molecular dynamics simulation studies of some novel kojic acid fused 2 amino 3 cyano 4h pyran derivatives as tyrosinase inhibitors |
| topic | Kojic acid Benzyloxy benzylidene 2-Amino-3-cyano-4H-pyran Molecular dynamics simulation Tyrosinase inhibitors |
| url | https://doi.org/10.1186/s13065-024-01134-1 |
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