Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Synthesis, Molecular Docking and α-Glucosidase Inhibitory Activity Study of 2,4,6-triaryl Pyrimidine Derivatives

Author(s): Mohammed Hussen Bule , Roghaieh Esfandyari, Tadesse Bekele Tafesse, Mohsen Amini*, Mohammad Ali Faramarzi and Mohammad Abdollahi

Volume 17, Issue 10, 2020

Page: [1216 - 1226] Pages: 11

DOI: 10.2174/1570180817666200103130536

Price: $65

Abstract

Background: α-Glucosidase inhibitors hinder the carbohydrate digestion and play an important role in the treatment of diabetes mellitus. α-glucosidase inhibitors available on the market are acarbose, miglitol, and voglibose. However, the use of acarbose is diminishing due to related side effects like diarrhea, bloating and abdominal distension.

Objectives: This study aimed to synthesize 2,4,6-triaryl pyrimidines derivatives, screen their α- glucosidase inhibitory activity, perform kinetic and molecular docking studies.

Methods: A series of 2,4,6-triaryl pyrimidine derivatives were synthesized and their α-glucosidase inhibitory activity was screened in vitro. Pyrimidine derivatives 4a-m were synthesized via a twostep reaction with a yield between 49 and 93%. The structure of the synthesized compounds was confirmed by different spectroscopic techniques (IR, NMR and MS). The in vitro α-glucosidase inhibition activities of the synthesized compounds 4a-m was also evaluated against Saccharomyces cerevisiae α-glucosidase.

Results and Discussion: The majority of synthesized compounds had α-glucosidase inhibitory activity. Particularly compounds 4b and 4g were the most active compounds with an IC50 value of 125.2± 7.2 and 139.8 ± 8.1 μM respectively. The kinetic study performed for the most active compound 4b revealed that the compound was a competitive inhibitor of Saccharomyces cerevisiae α-glucosidase with Ki of 122 μM. The molecular docking study also revealed that the two compounds have important binding interactions with the enzyme active site.

Conclusion: 2,4,6-triarylpyrimidine derivative 4a-m were synthesized and screened for α- glucosidase inhibitory activity. Most of the synthesized compounds possess α-glucosidase inhibitory activity, and compound 4b demonstrated the most significant inhibitory action as compared to acarbose.

Keywords: α-glucosidase inhibitor, pyrimidine, synthesis, enzyme assay, kinetic study, docking.

Graphical Abstract

[1]
Suresh, L.; Onkara, P.; Kumar, P.S.V.; Pydisetty, Y.; Chandramouli, G.V. Ionic liquid-promoted multicomponent synthesis of fused tetrazolo[1,5-a]pyrimidines as α-glucosidase inhibitors. Bioorg. Med. Chem. Lett., 2016, 26(16), 4007-4014.
[http://dx.doi.org/10.1016/j.bmcl.2016.06.086] [PMID: 27406797]
[2]
Javaid, K.; Saad, S.M.; Rasheed, S.; Moin, S.T.; Syed, N.; Fatima, I.; Salar, U.; Khan, K.M.; Perveen, S.; Choudhary, M.I. 2-Arylquinazolin-4(3H)-ones: A new class of α-glucosidase inhibitors. Bioorg. Med. Chem., 2015, 23(23), 7417-7421.
[http://dx.doi.org/10.1016/j.bmc.2015.10.038] [PMID: 26552899]
[3]
Yousefi, R.; Alavian-Mehr, M-M.; Mokhtari, F.; Panahi, F.; Mehraban, M.H.; Khalafi-Nezhad, A. Pyrimidine-fused heterocycle derivatives as a novel class of inhibitors for α-glucosidase. J. Enzyme Inhib. Med. Chem., 2013, 28(6), 1228-1235.
[http://dx.doi.org/10.3109/14756366.2012.727812] [PMID: 23043430]
[4]
Yin, Z.; Zhang, W.; Feng, F.; Zhang, Y.; Kang, W. α-Glucosidase inhibitors isolated from medicinal plants. Food Sci. Hum. Wellness, 2014, 3(3-4), 136-174.
[http://dx.doi.org/10.1016/j.fshw.2014.11.003]
[5]
Yar, M.; Bajda, M.; Shahzadi, L.; Shahzad, S.A.; Ahmed, M.; Ashraf, M.; Alam, U.; Khan, I.U.; Khan, A.F. Novel synthesis of dihydropyrimidines for α-glucosidase inhibition to treat Type 2 diabetes: In vitro biological evaluation and in silico docking. Bioorg. Chem., 2014, 54, 96-104.
[http://dx.doi.org/10.1016/j.bioorg.2014.05.003] [PMID: 24880489]
[6]
Mobinikhaledi, A.; Asghari, B.; Jabbarpour, M. Design and synthesis of new benzimidazole and pyrimidine derivatives as α - glucosidase inhibitor. I.J.P.R., , 2015, 14(3), 723 .
[7]
Barakat, A.; Islam, M.S.; Al-Majid, A.M.; Ghabbour, H.A.; Yousuf, S.; Ashraf, M.; Shaikh, N.N.; Iqbal Choudhary, M.; Khalil, R.; Ul-Haq, Z. Synthesis of pyrimidine-2,4,6-trione derivatives: Anti-oxidant, anti-cancer, α-glucosidase, β-glucuronidase inhibition and their molecular docking studies. Bioorg. Chem., 2016, 68, 72-79.
[http://dx.doi.org/10.1016/j.bioorg.2016.07.009] [PMID: 27454620]
[8]
Panahi, F.; Yousefi, R.; Mehraban, M.H.; Khalafi-Nezhad, A. Synthesis of new pyrimidine-fused derivatives as potent and selective antidiabetic α-glucosidase inhibitors. Carbohydr. Res., 2013, 380, 81-91.
[http://dx.doi.org/10.1016/j.carres.2013.07.008] [PMID: 23978663]
[9]
Liu, D.; Guo, W.; Wu, W.; Jiang, H. Base-Mediated three-component tandem reactions for the synthesis of multisubstituted pyrimidines. J. Org. Chem., 2017, 82(24), 13609-13616.
[http://dx.doi.org/10.1021/acs.joc.7b02113] [PMID: 29161041]
[10]
Guo, W. Base mediated direct C–H amination for pyrimidines synthesis from amidines and cinnamaldehydes using oxygen as green oxidants. Chin. Chem. Lett., 2016, 27(1), 47-50.
[http://dx.doi.org/10.1016/j.cclet.2015.09.012]
[11]
Vadagaonkar, K.S.; Kalmode, H.P.; Prakash, S.; Chaskar, A.C. Greener [3+ 3] tandem annulation-oxidation approach towards the synthesis of substituted pyrimidines. New J. Chem., 2015, 39(5), 3639-3645.
[http://dx.doi.org/10.1039/C4NJ02345E]
[12]
Gong, Z.; Xie, Z.; Qiu, J.; Wang, G. Synthesis, biological evaluation and molecular docking study of 2-substituted-4,6-diarylpyrimidines as α-glucosidase inhibitors. Molecules, 2017, 22(11), 1865.
[http://dx.doi.org/10.3390/molecules22111865] [PMID: 29084182]
[13]
Mishra, N.; Arora, P.; Kumar, B.; Mishra, L.C.; Bhattacharya, A.; Awasthi, S.K.; Bhasin, V.K. Synthesis of novel substituted 1,3-diaryl propenone derivatives and their antimalarial activity in vitro. Eur. J. Med. Chem., 2008, 43(7), 1530-1535.
[http://dx.doi.org/10.1016/j.ejmech.2007.09.014] [PMID: 17977622]
[14]
Ikeda, K.; Yomogita, A.; Kawamura, M.; Ono, H. Compound and organic electroluminescent element produced using same. 2016.U.S. Patent 9,508,939, .
[15]
Nikookar, H.; Mohammadi-Khanaposhtani, M.; Imanparast, S.; Faramarzi, M.A.; Ranjbar, P.R.; Mahdavi, M.; Larijani, B. Design, synthesis and in vitro α-glucosidase inhibition of novel dihydropyrano[3,2-c]quinoline derivatives as potential anti-diabetic agents. Bioorg. Chem., 2018, 77, 280-286.
[http://dx.doi.org/10.1016/j.bioorg.2018.01.025] [PMID: 29421703]
[16]
Rouzbehan, S.; Moein, S.; Homaei, A.; Moein, M.R. Kinetics of α-glucosidase inhibition by different fractions of three species of Labiatae extracts: A new diabetes treatment model. Pharm. Biol., 2017, 55(1), 1483-1488.
[http://dx.doi.org/10.1080/13880209.2017.1306569] [PMID: 28367665]
[17]
Imran, S.; Taha, M.; Ismail, N.H.; Kashif, S.M.; Rahim, F.; Jamil, W.; Hariono, M.; Yusuf, M.; Wahab, H. Synthesis of novel flavone hydrazones: in-vitro evaluation of α-glucosidase inhibition, QSAR analysis and docking studies. Eur. J. Med. Chem., 2015, 105, 156-170.
[http://dx.doi.org/10.1016/j.ejmech.2015.10.017] [PMID: 26491979]
[18]
Imran, S.; Taha, M.; Ismail, N.H.; Kashif, S.M.; Rahim, F.; Jamil, W.; Wahab, H.; Khan, K.M. Synthesis, in vitro and docking studies of new flavone ethers as α-glucosidase inhibitors. Chem. Biol. Drug Des., 2016, 87(3), 361-373.
[http://dx.doi.org/10.1111/cbdd.12666] [PMID: 26362113]
[19]
Kiefer, F.; Arnold, K.; Künzli, M.; Bordoli, L.; Schwede, T. The SWISS-MODEL Repository and associated resources. Nucleic Acids Res., , 2008, 37(suppl_1 ), D387-D392.
[20]
ChemAxon. MarvinSketch 19.1. ChemAxon Budapest,, , 2018.https://chemaxon.com/products/marvin
[21]
AutoDockTools. the free GUI for AutoDock. , http://autodock.scripps.edu/resources/adt
[22]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[23]
Schrodinger, L.L.C. 2015.https://www.schrodinger.com/pymol
[24]
Visualizer, D.S. Accelrys software inc Discovery Studio Visualizer, 2017.https://www.3dsbiovia.com/products/collaborative-science/biovia-discovery-studio/visualization-download.php
[25]
Mohammadi-Khanaposhtani, M.; Yahyavi, H.; Barzegaric, E.; Imanparast, S.; Heravi, M. M.; Ali Faramarzi, M.; Foroumadi, A.; Adibi, H.; Larijani, B.; Mahdavi, M. New biscoumarin derivatives as potent α-glucosidase Inhibitors: Synthesis, biological evaluation, kinetic analysis, and docking study. Polycycl. Aromat. Comp., , 2018, 1-12.
[26]
Bhat, A.R.; Dongre, R.S.; Naikoo, G.A.; Hassan, I.U.; Ara, T. Proficient synthesis of bioactive annulated pyrimidine derivatives: A review. J. Taibah. Univ. Sci., 2017, 11, 1047-1069.
[http://dx.doi.org/10.1016/j.jtusci.2017.05.005]
[27]
Mahfoudh, M.; Abderrahim, R.; Leclerc, E.; Campagne, J.M. Recent approaches to the synthesis of pyrimidine derivatives. Eur. J. Org. Chem., 2017, 2856-2865.
[http://dx.doi.org/10.1002/ejoc.201700008]
[28]
Chen, L.; Jin, Y.; Fu, W.; Xiao, S.; Feng, C.; Fang, B.; Gu, Y.; Li, C.; Zhao, Y.; Liu, Z.; Liang, G. Design, synthesis, and structure-activity relationship analysis of thiazolo[3,2-a]pyrimidine derivatives with anti-inflammatory activity in acute lung injury. ChemMedChem, 2017, 12(13), 1022-1032.
[http://dx.doi.org/10.1002/cmdc.201700175] [PMID: 28503918]
[29]
Hill, M.D.; Movassaghi, M. New strategies for the synthesis of pyrimidine derivatives. Chemistry, 2008, 14(23), 6836-6844.
[http://dx.doi.org/10.1002/chem.200800014] [PMID: 18384023]
[30]
Joshi, V.D.; Kshirsagar, M.D.; Singhal, S. Synthesis and pharmacological study of some novel pyrimidines. Pharm. Sin., 2012, 3, 343-348.
[31]
Kumar, B.; Kumar, M.; Dwivedi, A.R.; Kumar, V. Synthesis, biological evaluation and molecular modeling studies of propargyl containing 2,4,6-trisubstituted pyrimidine derivatives as potential anti-Parkinson agents. ChemMedChem, 2018, 13(7), 705-712.
[http://dx.doi.org/10.1002/cmdc.201700589] [PMID: 29534334]
[32]
Wu, P.; Cai, X.M.; Wang, Q.F.; Yan, C.G. Facile synthesis of triarylpyrimidines with Microwave-irradiated reactions of n-phenacylpyridinium chloride. Synth. Commun., 2007, 37, 223-229.
[http://dx.doi.org/10.1080/00397910601031843]
[33]
Yousefi, A.; Yousefi, R.; Panahi, F.; Sarikhani, S.; Zolghadr, A.R.; Bahaoddini, A.; Khalafi-Nezhad, A. Novel curcumin-based pyrano[2,3-d]pyrimidine anti-oxidant inhibitors for α-amylase and α-glucosidase: Implications for their pleiotropic effects against diabetes complications. Int. J. Biol. Macromol., 2015, 78, 46-55.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.03.060] [PMID: 25843662]
[34]
Shahidpour, S.; Panahi, F.; Yousefi, R.; Nourisefat, M.; Nabipoor, M.; Khalafi-Nezhad, A. Design and synthesis of new antidiabetic α-glucosidase and α-amylase inhibitors based on pyrimidine-fused heterocycles. Med. Chem. Res., 2015, 24, 3086-3096.
[http://dx.doi.org/10.1007/s00044-015-1356-2]
[35]
El-Fal, M.; Sayah, K.; Marmouzi, I.; Faouzi, M.E.A.; Ansar, M.h.; Taoufik, J.; Essassi, E.M.; Ramli, Y. Synthesis, and evaluation of α-amylase and α-glucosidase inhibitory potential of new pyrazolo [3, 4-d] pyrimidine derivatives. Eur. J. Chem., 2017, 8, 105-108.
[http://dx.doi.org/10.5155/eurjchem.8.2.105-108.1541]
[36]
Thakur, R.K.; Mishra, A.; Ramakrishna, K.; Mahar, R.; Shukla, S.K.; Srivastava, A.; Tripathi, R.P. Synthesis of novel pyrimidine nucleoside analogues owning multiple bases/sugars and their glycosidase inhibitory activity. Tetrahedron, 2014, 70(45), 8462-8473.
[http://dx.doi.org/10.1016/j.tet.2014.09.078]
[37]
Kumar, S.; Lim, S.M.; Ramasamy, K.; Vasudevan, M.; Shah, S.A.A.; Selvaraj, M.; Narasimhan, B. Synthesis, molecular docking and biological evaluation of bis-pyrimidine Schiff base derivatives. Chem. Cent. J., 2017, 11(1), 89.
[http://dx.doi.org/10.1186/s13065-017-0322-0] [PMID: 29086867]
[38]
Bajda, M.; Boryczka, S.; Wietrzyk, J.; Malawska, B. Investigation of lipophilicity of anticancer-active thioquinoline derivatives. Biomed. Chromatogr., 2007, 21(2), 123-131.
[http://dx.doi.org/10.1002/bmc.706] [PMID: 17120300]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy