Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitors
Objective(s): In the present study,a new series of 6-methoxy-2-arylquinoline analogues was designed and synthesized as P-glycoprotein (P-gp) inhibitors using quinine and flavones as the lead compounds. Materials and Methods: The cytotoxic activity of the synthesized compounds was evaluated against t...
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| Format: | Article |
| Language: | English |
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Mashhad University of Medical Sciences
2018-01-01
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| Series: | Iranian Journal of Basic Medical Sciences |
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| Online Access: | http://ijbms.mums.ac.ir/article_9917_8ed4de841fcb62e0e8ed927ed1bc91b4.pdf |
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| author | Sayyed Mohammad Abutorabzadeh Fatemeh Mosafa Farzin Hadizadeh Razieh Ghodsi |
| author_facet | Sayyed Mohammad Abutorabzadeh Fatemeh Mosafa Farzin Hadizadeh Razieh Ghodsi |
| author_sort | Sayyed Mohammad Abutorabzadeh |
| collection | DOAJ |
| description | Objective(s): In the present study,a new series of 6-methoxy-2-arylquinoline analogues was designed and synthesized as P-glycoprotein (P-gp) inhibitors using quinine and flavones as the lead compounds. Materials and Methods: The cytotoxic activity of the synthesized compounds was evaluated against two human cancer cell lines including EPG85-257RDB, multidrug-resistant gastric carcinoma cells (P-gp-positive gastric carcinoma cell line), and EPG85-257P, drug-sensitive gastric carcinoma cells. Compounds showing low to moderate toxicity in the MTT test were selected to investigate their P-gp inhibition activity. Moreover, trying to explain the results of biological experiments, docking studies of the selected compounds into the homology-modeled human P-gp, were carried out. The physicochemical and ADME properties of the compounds as drug candidate were also predicted. Results: Most of our compounds exhibited negligible or much lower cytotoxic effect in both cancer cells. Among the series, 5a and 5b, alcoholic quinoline derivatives were found to inhibit the efflux of rhodamine 123 at the concentration of 10 μM significantly. Conclusion: Among the tested quinolines, 5a and 5b showed the most potent P-gp inhibitory activity in the series and were 1.3-fold and 2.1-fold stronger than verapamil, respectively. SAR data revealed that hydroxyl methyl in position 4 of quinolines has a key role in P-gp efflux inhibition of our compounds. ADME studies suggested that all of the compounds included in this study may have a good human intestinal absorption. |
| first_indexed | 2024-12-11T11:54:13Z |
| format | Article |
| id | doaj.art-846613d3910349c08eaabd7ca7f22d88 |
| institution | Directory Open Access Journal |
| issn | 2008-3866 2008-3874 |
| language | English |
| last_indexed | 2024-12-11T11:54:13Z |
| publishDate | 2018-01-01 |
| publisher | Mashhad University of Medical Sciences |
| record_format | Article |
| series | Iranian Journal of Basic Medical Sciences |
| spelling | doaj.art-846613d3910349c08eaabd7ca7f22d882022-12-22T01:08:15ZengMashhad University of Medical SciencesIranian Journal of Basic Medical Sciences2008-38662008-38742018-01-0121191810.22038/ijbms.2017.24476.60929917Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitorsSayyed Mohammad Abutorabzadeh0Fatemeh Mosafa1Farzin Hadizadeh2Razieh Ghodsi3Biotechnology Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran|Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, IranBiotechnology Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, IranBiotechnology Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran|Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, IranBiotechnology Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran|Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, IranObjective(s): In the present study,a new series of 6-methoxy-2-arylquinoline analogues was designed and synthesized as P-glycoprotein (P-gp) inhibitors using quinine and flavones as the lead compounds. Materials and Methods: The cytotoxic activity of the synthesized compounds was evaluated against two human cancer cell lines including EPG85-257RDB, multidrug-resistant gastric carcinoma cells (P-gp-positive gastric carcinoma cell line), and EPG85-257P, drug-sensitive gastric carcinoma cells. Compounds showing low to moderate toxicity in the MTT test were selected to investigate their P-gp inhibition activity. Moreover, trying to explain the results of biological experiments, docking studies of the selected compounds into the homology-modeled human P-gp, were carried out. The physicochemical and ADME properties of the compounds as drug candidate were also predicted. Results: Most of our compounds exhibited negligible or much lower cytotoxic effect in both cancer cells. Among the series, 5a and 5b, alcoholic quinoline derivatives were found to inhibit the efflux of rhodamine 123 at the concentration of 10 μM significantly. Conclusion: Among the tested quinolines, 5a and 5b showed the most potent P-gp inhibitory activity in the series and were 1.3-fold and 2.1-fold stronger than verapamil, respectively. SAR data revealed that hydroxyl methyl in position 4 of quinolines has a key role in P-gp efflux inhibition of our compounds. ADME studies suggested that all of the compounds included in this study may have a good human intestinal absorption.http://ijbms.mums.ac.ir/article_9917_8ed4de841fcb62e0e8ed927ed1bc91b4.pdfMolecular dockingP-glycoproteinP-gp inhibitionQuinolineSynthesis |
| spellingShingle | Sayyed Mohammad Abutorabzadeh Fatemeh Mosafa Farzin Hadizadeh Razieh Ghodsi Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitors Iranian Journal of Basic Medical Sciences Molecular docking P-glycoprotein P-gp inhibition Quinoline Synthesis |
| title | Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitors |
| title_full | Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitors |
| title_fullStr | Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitors |
| title_full_unstemmed | Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitors |
| title_short | Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitors |
| title_sort | design synthesis and biological evaluation of 6 methoxy 2 arylquinolines as potential p glycoprotein inhibitors |
| topic | Molecular docking P-glycoprotein P-gp inhibition Quinoline Synthesis |
| url | http://ijbms.mums.ac.ir/article_9917_8ed4de841fcb62e0e8ed927ed1bc91b4.pdf |
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