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Current Enzyme Inhibition

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ISSN (Print): 1573-4080
ISSN (Online): 1875-6662

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Research Article

Enzyme Inhibition, Kinetic, and Molecular Docking Studies of α-glucosidase

Author(s): Ebrahim S. Moghadam, Mohammad A. Faramarzi, Somayeh Imanparast and Mohsen Amini*

Volume 16, Issue 2, 2020

Page: [155 - 161] Pages: 7

DOI: 10.2174/1573408016999200415115009

Price: $65

Abstract

Background: Diabetes mellitus (DM) is an important global health problem especially in developed countries and insufficient lifestyle induces this phenomenon. Finding efficient treatment for DM is an interesting goal for researchers.

Objective: Herein we tried to design and synthesize a series of quinazoline derivatives and investigate their bioactivity as possible α-Glucosidase inhibitor agents.

Method: Compounds 1-14 were synthesized using a multicomponent reaction. 1HNMR, 13C NMR, MS, and IR spectroscopy were used for the characterization of synthesized compounds. α- Glucosidase inhibitory activity of compounds 1-14 was evaluated using p-nitrophenyl‐α‐Dglucopyranoside (pNPG) as a substrate of the α-glucosidase enzyme (EC3.2.1.20, Saccharomyces cerevisiae). The mechanism of inhibition of the α-glucosidase enzyme was investigated using kinetic studies. Molecular docking was also done using autodock software to find the possible mode of interaction of compound 8 and the enzyme active site.

Results: Most of the tested compounds showed higher activity in inhibition of the enzyme in comparison to the standard, acarbose. Compound 8 exerted the best activity with the IC50 value of 291.5 μM. A kinetic study indicated a competitive inhibition of the α-glucosidase enzyme by compound 8. Finally, docking studies showed the interactions between compound 8 and enzyme active site residues.

Conclusion: 2,4-Diarylquinazoline scaffold has good antidiabetic activity, so it is interesting to synthesize more 2,4-diarylquinazoline derivatives and evaluate their antidiabetic activities.

Keywords: Diabetes, docking, drug design, kinetic study, quinazoline, synthesis, α-Glucosidase.

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[1]
Wang, G.; Chen, M.; Qiu, J.; Xie, Z.; Cao, A. Synthesis, in vitro α-glucosidase inhibitory activity and docking studies of novel chromone-isatin derivatives. Bioorg. Med. Chem. Lett., 2018, 28(2), 113-116.
[http://dx.doi.org/10.1016/j.bmcl.2017.11.047] [PMID: 29208524]
[2]
Luthra, T.; Banothu, V.; Adepally, U.; Kumar, K.; M, S.; Chakrabarti, S.; Maddi, S.R.; Sen, S. Discovery of novel pyrido-pyrrolidine hybrid compounds as alpha-glucosidase inhibitors and alternative agent for control of type 1 diabetes. Eur. J. Med. Chem., 2020, 188112034
[http://dx.doi.org/10.1016/j.ejmech.2020.112034] [PMID: 31927314]
[3]
Ali, F.; Khan, K.M.; Salar, U.; Taha, M.; Ismail, N.H.; Wadood, A.; Riaz, M.; Perveen, S. Hydrazinyl arylthiazole based pyridine scaffolds: Synthesis, structural characterization, in vitro α-glucosidase inhibitory activity, and in silico studies. Eur. J. Med. Chem., 2017, 138, 255-272.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.041] [PMID: 28672278]
[4]
Kasturi, S.P.; Surarapu, S.; Uppalanchi, S.; Dwivedi, S.; Yogeeswari, P.; Sigalapalli, D.K.; Bathini, N.B.; Ethiraj, K.S.; Anireddy, J.S. Synthesis, molecular modeling and evaluation of α-glucosidase inhibition activity of 3,4-dihydroxy piperidines. Eur. J. Med. Chem., 2018, 150, 39-52.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.072] [PMID: 29518717]
[5]
Cai, C.Y.; Rao, L.; Rao, Y.; Guo, J.X.; Xiao, Z.Z.; Cao, J.Y.; Huang, Z.S.; Wang, B. Analogues of xanthones--Chalcones and bis-chalcones as α-glucosidase inhibitors and anti-diabetes candidates. Eur. J. Med. Chem., 2017, 130, 51-59.
[http://dx.doi.org/10.1016/j.ejmech.2017.02.007] [PMID: 28242551]
[6]
Liu, X.; Zang, X.; Yin, X.; Yang, W.; Huang, J.; Huang, J.; Yu, C.; Ke, C.; Hong, Y. Semi-synthesis of C28-modified triterpene acid derivatives from maslinic acid or corosolic acid as potential α-glucosidase inhibitors. Bioorg. Chem., 2020, 97103694
[http://dx.doi.org/10.1016/j.bioorg.2020.103694] [PMID: 32120080]
[7]
Mphahlele, M.J.; Magwaza, N.M.; Gildenhuys, S.; Setshedi, I.B. Synthesis, α-glucosidase inhibition and antioxidant activity of the 7-carbo-substituted 5-bromo-3-methylindazoles. Bioorg. Chem., 2020, 97103702
[http://dx.doi.org/10.1016/j.bioorg.2020.103702] [PMID: 32146175]
[8]
Yang, X.T.; Geng, C.A.; Li, T.Z.; Deng, Z.T.; Chen, J.J. Synthesis and biological evaluation of chepraecoxin A derivatives as α-glucosidase inhibitors. Bioorg. Med. Chem. Lett., 2020, 30(8)127020
[http://dx.doi.org/10.1016/j.bmcl.2020.127020] [PMID: 32067867]
[9]
Kim, J.H.; Cho, C.W.; Lee, J.I.; Vinh, L.B.; Kim, K.T.; Cho, I.S. An investigation of the inhibitory mechanism of α-glucosidase by chysalodin from Aloe vera. Int. J. Biol. Macromol., 2020, 147, 314-318.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.01.076] [PMID: 31926229]
[10]
Kawde, A.N.; Taha, M.; Alansari, R.S.; Almandil, N.B.; Anouar, E.H.; Uddin, N.; Rahim, F.; Chigurupati, S.; Nawaz, M.; Hayat, S.; Ibrahim, M.; Elakurthy, P.K.; Vijayan, V.; Morsy, M.; Ibrahim, H.; Baig, N.; Khan, K.M. Exploring efficacy of indole-based dual inhibitors for α-glucosidase and α-amylase enzymes: In silico, biochemical and kinetic studies. Int. J. Biol. Macromol., 2020, 154, 217-232.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.03.090] [PMID: 32173438]
[11]
Ou-Yang, C.; Chai, W.; Xu, X.; Song, S.; Wei, Q.; Huang, Q.; Zou, Z. Inhibitory potential of proanthocyanidins from the fruit pulp of Clausena lansium (Lour.) Skeels against _-glucosidase and non-enzymatic glycation: activity and mechanism. Process Biochem.,
[http://dx.doi.org/10.1016/j.procbio.2020.01.006]
[12]
Sun, H.; Ding, W.; Song, X.; Wang, D.; Chen, M.; Wang, K.; Zhang, Y.; Yuan, P.; Ma, Y.; Wang, R.; Dodd, R.H.; Zhang, Y.; Lu, K.; Yu, P. Synthesis of 6-hydroxyaurone analogues and evaluation of their α-glucosidase inhibitory and glucose consumption-promoting activity: Development of highly active 5,6-disubstituted derivatives. Bioorg. Med. Chem. Lett., 2017, 27(15), 3226-3230.
[http://dx.doi.org/10.1016/j.bmcl.2017.06.040] [PMID: 28651984]
[13]
Ding, S.M.; Lan, T.; Ye, G.J.; Huang, J.J.; Hu, Y.; Zhu, Y.R.; Wang, B. Novel oxazolxanthone derivatives as a new type of α-glucosidase inhibitor: synthesis, activities, inhibitory modes and synergetic effect. Bioorg. Med. Chem., 2018, 26(12), 3370-3378.
[http://dx.doi.org/10.1016/j.bmc.2018.05.008] [PMID: 29776833]
[14]
Xu, X.T.; Deng, X.Y.; Chen, J.; Liang, Q.M.; Zhang, K.; Li, D.L.; Wu, P.P.; Zheng, X.; Zhou, R.P.; Jiang, Z.Y.; Ma, A.J.; Chen, W.H.; Wang, S.H. Synthesis and biological evaluation of coumarin derivatives as α-glucosidase inhibitors. Eur. J. Med. Chem., 2020, 189112013
[http://dx.doi.org/10.1016/j.ejmech.2019.112013] [PMID: 31972390]
[15]
Baumann, M.; Baxendale, I.R. An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles. Beilstein J. Org. Chem., 2013, 9, 2265-2319.
[http://dx.doi.org/10.3762/bjoc.9.265] [PMID: 24204439]
[16]
Baumann, M.; Baxendale, I.R.; Ley, S.V.; Nikbin, N. An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals. Beilstein J. Org. Chem., 2011, 7, 442-495.
[http://dx.doi.org/10.3762/bjoc.7.57] [PMID: 21647262]
[17]
Gurram, V.; Garlapati, R.; Thulluri, C.; Madala, N.; Kasani, K.S.; Machiraju, P.K.; Doddapalla, R.; Addepally, U.; Gundla, R.; Patro, B.; Pottabathini, N. Design, synthesis, and biological evaluation of quinazoline derivatives as a-glucosidase inhibitors. Med. Chem. Res., 2015, 24, 2227-2237.
[http://dx.doi.org/10.1007/s00044-014-1293-5]
[18]
Nara, H.; Sato, K.; Naito, T.; Mototani, H.; Oki, H.; Yamamoto, Y.; Kuno, H.; Santou, T.; Kanzaki, N.; Terauchi, J.; Uchikawa, O.; Kori, M. Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach. J. Med. Chem., 2014, 57(21), 8886-8902.
[http://dx.doi.org/10.1021/jm500981k] [PMID: 25264600]
[19]
Herget, T.; Freitag, M.; Morbitzer, M.; Kupfer, R.; Stamminger, T.; Marschall, M. Novel chemical class of pUL97 protein kinase-specific inhibitors with strong anticytomegaloviral activity. Antimicrob. Agents Chemother., 2004, 48(11), 4154-4162.
[http://dx.doi.org/10.1128/AAC.48.11.4154-4162.2004] [PMID: 15504835]
[20]
Roecker, A.J.; Mercer, S.P.; Bergman, J.M.; Gilbert, K.F.; Kuduk, S.D.; Harrell, C.M.; Garson, S.L.; Fox, S.V.; Gotter, A.L.; Tannenbaum, P.L.; Prueksaritanont, T.; Cabalu, T.D.; Cui, D.; Lemaire, W.; Winrow, C.J.; Renger, J.J.; Coleman, P.J. Discovery of diazepane amide DORAs and 2-SORAs enabled by exploration of isosteric quinazoline replacements. Bioorg. Med. Chem. Lett., 2015, 25(21), 4992-4999.
[http://dx.doi.org/10.1016/j.bmcl.2014.12.081] [PMID: 25613676]
[21]
Lim, C.J.; Oh, K.S.; Ha, J.D.; Lee, J.H.; Seo, H.W.; Chae, C.H.; Kim, D.G.; Lee, M.J.; Lee, B.H. 4-Substituted quinazoline derivatives as novel EphA2 receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(17), 4080-4083.
[http://dx.doi.org/10.1016/j.bmcl.2014.07.081] [PMID: 25124116]
[22]
Xiao, H.; Li, P.; Hu, D.; Song, B-A. Synthesis and anti-TMV activity of novel β-amino acid ester derivatives containing quinazoline and benzothiazole moieties. Bioorg. Med. Chem. Lett., 2014, 24(15), 3452-3454.
[http://dx.doi.org/10.1016/j.bmcl.2014.05.073] [PMID: 24934508]
[23]
Hamed, M.M.; Abou El Ella, D.A.; Keeton, A.B.; Piazza, G.A.; Abadi, A.H.; Hartmann, R.W.; Engel, M. 6-Aryl and heterocycle quinazoline derivatives as potent EGFR inhibitors with improved activity toward gefitinib-sensitive and -resistant tumor cell lines. ChemMedChem, 2013, 8(9), 1495-1504.
[http://dx.doi.org/10.1002/cmdc.201300147] [PMID: 23847159]
[24]
Marugan, J.J.; Zheng, W.; Motabar, O.; Southall, N.; Goldin, E.; Westbroek, W.; Stubblefield, B.K.; Sidransky, E.; Aungst, R.A.; Lea, W.A.; Simeonov, A.; Leister, W.; Austin, C.P. Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity. J. Med. Chem., 2011, 54(4), 1033-1058.
[http://dx.doi.org/10.1021/jm1008902] [PMID: 21250698]
[25]
Saeedian Moghadam, E. Hossein poor Tehrani, M.; Faramarzi, M.A.; Abadian, N.; Amini, M. 2,4-Disubstituted Quinazoline Derivatives Act as Inducers of Tubulin Polymerization: Synthesis and Cytotoxicity. Anticancer. Agents Med. Chem., 2019.
[http://dx.doi.org/10.2174/1871520619666190314125254]
[26]
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]
[27]
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]
[28]
Hati, S.; Madurkar, S.M.; Bathula, C.; Thulluri, C.; Agarwal, R.; Siddiqui, F.A.; Dangi, P.; Adepally, U.; Singh, A.; Singh, S.; Sen, S. Design, synthesis and biological evaluation of small molecules as potent glucosidase inhibitors. Eur. J. Med. Chem., 2015, 100, 188-196.
[http://dx.doi.org/10.1016/j.ejmech.2015.04.059] [PMID: 26087029]
[29]
Khosravi, A.; Vaezi, G.; Hojati, V.; Abdi, K. Study on the interaction of triaryl-dihydro-1,2,4-oxadiazoles with α-glucosidase. Daru, 2020.
[http://dx.doi.org/10.1007/s40199-019-00322-y] [PMID: 31907787]

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