Abstract
Background: α-Glucosidase inhibitors have occupied a significant position in the treatment of type 2 diabetes. In this respect, the development of novel and efficient non-sugar-based inhibitors is in high demand.
Objective: Design and synthesis of new 5-arylisoxazole-1,3,4-thiadiazole hybrids possessing α- glucosidase inhibitory activity were developed.
Methods: Different derivatives were synthesized by the reaction of various 5-arylisoxazole-3- carboxylic acids and ethyl 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)acetate. Finally, they were evaluated for their α-glucosidase inhibitory activity.
Results: It was found that ethyl 2-((5-(5-(2-chlorophenyl)isoxazole-3-carboxamido)-1,3,4-thiadiazol- 2-yl)thio)acetate (5j) was the most potent compound (IC50 = 180.1 μM) compared with acarbose as the reference drug (IC50 = 750.0 μM). Also, the kinetic study of 5j revealed a competitive inhibition and docking study results indicated desired interactions of that compound with amino acid residues located close to the active site of α-glucosidase.
Conclusion: Good α-glucosidase inhibitory activity obtained by the title compounds introduced them as an efficient scaffold, which merits to be considered in anti-diabetic drug discovery developments.
Keywords: 5-Arylisoxazole, docking, α-glucosidase, kinetic study, 1, 3, 4-thiadiazole, synthesis.
Graphical Abstract
[3]
van de Laar, F.A.; Lucassen, P.L.; Akkermans, R.P.; van de Lisdonk, E.H.; Rutten, G.E.; van Weel, C. α -glucosidase inhibitors for patients with type 2 diabetes: Results from a Cochrane systematic review and meta-analysis. Diabetes Care, 2005, 28(1), 154-163.
[http://dx.doi.org/10.2337/diacare.28.1.154] [PMID: 15616251]
[http://dx.doi.org/10.2337/diacare.28.1.154] [PMID: 15616251]
[4]
Saeedi, M.; Hadjiakhondi, A.; Nabavi, S.M.; Manayi, A. Heterocyclic Compounds: Effective α-Amylase and α-Glucosidase Inhibitors. Curr. Top. Med. Chem., 2017, 17(4), 428-440.
[http://dx.doi.org/10.2174/1568026616666160824104655] [PMID: 27558678]
[http://dx.doi.org/10.2174/1568026616666160824104655] [PMID: 27558678]
[5]
Liu, Z.; Ma, S. Recent advances in synthetic α -glucosidase inhibitors. ChemMedChem, 2017, 12(11), 819-829.
[http://dx.doi.org/10.1002/cmdc.201700216] [PMID: 28498640]
[http://dx.doi.org/10.1002/cmdc.201700216] [PMID: 28498640]
[6]
Dhameja, M.; Gupta, P. Synthetic heterocyclic candidates as promising α -glucosidase inhibitors: An overview. Eur. J. Med. Chem., 2019, 176, 343-377.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.025] [PMID: 31112894]
[http://dx.doi.org/10.1016/j.ejmech.2019.04.025] [PMID: 31112894]
[7]
van de Laar, F.A. Alpha-glucosidase inhibitors in the early treatment of type 2 diabetes. Vasc. Health Risk Manag., 2008, 4(6), 1189-1195.
[http://dx.doi.org/10.2147/VHRM.S3119] [PMID: 19337532]
[http://dx.doi.org/10.2147/VHRM.S3119] [PMID: 19337532]
[8]
Saeedi, M.; Mohammadi-Khanaposhtani, M.; Asgari, M.S.; Eghbalnejad, N.; Imanparast, S.; Faramarzi, M.A.; Larijani, B.; Mahdavi, M.; Akbarzadeh, T. Design, synthesis, in vitro, and in silico studies of novel diarylimidazole-1,2,3-triazole hybrids as potent α-glucosidase inhibitors. Bioorg. Med. Chem., 2019, 27(23), 115148.
[http://dx.doi.org/10.1016/j.bmc.2019.115148] [PMID: 31679980]
[http://dx.doi.org/10.1016/j.bmc.2019.115148] [PMID: 31679980]
[9]
Kaur, R.; Palta, K.; Kumar, M. Hybrids of isatin-pyrazole as potential α-glucosidase inhibitors: synthesis, biological evaluations and molecular docking studies. ChemistrySelect, 2019, 4, 13219-13227.
[http://dx.doi.org/10.1002/slct.201903418]
[http://dx.doi.org/10.1002/slct.201903418]
[10]
Rafique, R.; Khan, K.M. Arshia; Kanwal; Chigurupati, S.; Wadood, A.; Rehman, A.U.; Karunanidhi, A.; Hameed, S.; Taha, M.; Al-Rashida, M. Synthesis of new indazole based dual inhibitors of α -glucosidase and α-amylase enzymes, their in vitro, in silico and kinetics studies. Bioorg. Chem., 2020, 94, 103195.
[http://dx.doi.org/10.1016/j.bioorg.2019.103195] [PMID: 31451297]
[http://dx.doi.org/10.1016/j.bioorg.2019.103195] [PMID: 31451297]
[11]
Hameed, S. Kanwal; Seraj, F.; Rafique, R.; Chigurupati, S.; Wadood, A.; Rehman, A.U.; Venugopal, V.; Salar, U.; Taha, M.; Khan, K.M. Synthesis of benzotriazoles derivatives and their dual potential as α-amylase and α-glucosidase inhibitors in vitro: Structure-activity relationship, molecular docking, and kinetic studies. Eur. J. Med. Chem., 2019, 183, 111677.
[http://dx.doi.org/10.1016/j.ejmech.2019.111677] [PMID: 31514061]
[http://dx.doi.org/10.1016/j.ejmech.2019.111677] [PMID: 31514061]
[12]
Yousuf, H.; Shamim, S.; Khan, K.M.; Chigurupati, S. Kanwal, Hameed, S.; Khan, M.N.; Taha, M.; Arfeen, M. Dihydropyridines as potential α-amylase and α-glucosidase inhibitors: Synthesis, in vitro and in silico studies. Bioorg. Chem., 2020, 96, 103581.
[http://dx.doi.org/10.1016/j.bioorg.2020.103581] [PMID: 31978686]
[http://dx.doi.org/10.1016/j.bioorg.2020.103581] [PMID: 31978686]
[13]
Pogaku, V.; Gangarapu, K.; Basavoju, S.; Tatapudi, K.K.; Katragadda, S.B. Design, synthesis, molecular modelling, ADME prediction and anti-hyperglycemic evaluation of new pyrazole-triazolopyrimidine hybrids as potent α-glucosidase inhibitors. Bioorg. Chem., 2019, 93, 103307.
[http://dx.doi.org/10.1016/j.bioorg.2019.103307] [PMID: 31585262]
[http://dx.doi.org/10.1016/j.bioorg.2019.103307] [PMID: 31585262]
[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, 189, 112013.
[http://dx.doi.org/10.1016/j.ejmech.2019.112013] [PMID: 31972390]
[http://dx.doi.org/10.1016/j.ejmech.2019.112013] [PMID: 31972390]
[15]
Taha, M.; Alshamrani, F.J.; Rahim, F.; Hayat, S.; Ullah, H.; Zaman, K.; Imran, S.; Khan, K.M.; Naz, F. Synthesis of novel triazinoindole-based thiourea hybrid: A study on α-glucosidase inhibitors and their molecular docking. Molecules, 2019, 24(21), 3819.
[http://dx.doi.org/10.3390/molecules24213819] [PMID: 31652777]
[http://dx.doi.org/10.3390/molecules24213819] [PMID: 31652777]
[16]
Taha, M.; Ismail, N.H.; Imran, S.; Ainaa, I.; Selvaraj, M.; Baharudin, M.S.; Ali, M.; Khan, K.M.; Uddin, N. Synthesis of 2-phenyl-1H-imidazo[4,5-b]pyridine as type 2 diabetes inhibitors and molecular docking studies. Med. Chem. Res., 2017, 26, 916-928.
[http://dx.doi.org/10.1007/s00044-017-1806-0]
[http://dx.doi.org/10.1007/s00044-017-1806-0]
[17]
Javid, M.T.; Rahim, F.; Taha, M.; Ur Rehman, H.; Nawaz, M. wadood, A.; Imran, S.; Uddin, I.; Mosaddik, A.; Khan, K.M. Synthesis, in vitro α-glucosidase inhibitory potential and molecular docking study of thiadiazole analogs. Bioorg. Chem., 2018, 78, 201-209.
[http://dx.doi.org/10.1016/j.bioorg.2018.03.022] [PMID: 29597114]
[http://dx.doi.org/10.1016/j.bioorg.2018.03.022] [PMID: 29597114]
[18]
Vafadarnejad, F.; Karimpour-Razkenari, E.; Sameem, B.; Saeedi, M.; Firuzi, O.; Edraki, N.; Mahdavi, M.; Akbarzadeh, T. Novel N-benzylpyridinium moiety linked to arylisoxazole derivatives as selective butyrylcholinesterase inhibitors: Synthesis, biological evaluation, and docking study. Bioorg. Chem., 2019, 92, 103192.
[http://dx.doi.org/10.1016/j.bioorg.2019.103192] [PMID: 31446239]
[http://dx.doi.org/10.1016/j.bioorg.2019.103192] [PMID: 31446239]
[19]
Saeedi, M.; Rastegari, A.; Hariri, R.; Mirfazli, S.S.; Mahdavi, M.; Edraki, N.; Firuzi, O.; Akbarzadeh, T. Design and synthesis of novel arylisoxazole-chromenone carboxamides: Investigation of biological activities associated with Alzheimer’s disease. Chem. Biodivers., 2020, 17(5), e1900746.
[http://dx.doi.org/10.1002/cbdv.201900746] [PMID: 32154628]
[http://dx.doi.org/10.1002/cbdv.201900746] [PMID: 32154628]
[20]
Saeedi, M.; Hashemi, M.; Mahdavi, M.; Rafinejad, A.; Najafi, Z.; Mirfazli, S.S.; Mohammadian, R.; Karimpour-Razkenari, E.; Ardestani, S.K.; Safavi, M.; Akbarzadeh, T. Synthesis and anticancer activity of N-(di/trimethoxyaryl)-5-arylisoxazole-3-carboxamide. Polycycl. Aromat. Compd., 2019, 1568-1580.
[http://dx.doi.org/10.1080/10406638.2018.1564677]
[http://dx.doi.org/10.1080/10406638.2018.1564677]
[21]
Kang, Y.K.; Shin, K.J.; Yoo, K.H.; Seo, K.J.; Hong, C.Y.; Lee, C.S.; Park, S.Y.; Kim, D.J.; Park, S.W. Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety. Bioorg. Med. Chem., 2000, 10(2), 95-99.
[http://dx.doi.org/10.1016/S0960-894X(99)00646-0] [PMID: 10673088]
[http://dx.doi.org/10.1016/S0960-894X(99)00646-0] [PMID: 10673088]
[22]
Trefzger, O.S.; Barbosa, N.V.; Scapolatempo, R.L. das Neves, A.R.; Ortale, M.L.F.S.; Carvalho, D.B.; Honorato, A.M.; Fragoso, M.R.; Shuiguemoto, C.Y.K.; Perdomo, R.T.; Matos, M.F.C.; Chang, M.R.; Arruda, C.C.P.; Baroni, A.C.M. Design, synthesis, antileishmanial, and antifungal biological evaluation of novel 3,5-disubstituted isoxazole compounds based on 5-nitrofuran scaffolds. Arch. Pharm, 2020, 353, 1900241.
[http://dx.doi.org/10.1002/ardp.201900241]
[http://dx.doi.org/10.1002/ardp.201900241]
[23]
Egorova, A.; Kazakova, E.; Jahn, B.; Ekins, S.; Makarov, V.; Schmidtke, M. Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses. Eur. J. Med. Chem., 2020, 188, 112007.
[http://dx.doi.org/10.1016/j.ejmech.2019.112007] [PMID: 31881489]
[http://dx.doi.org/10.1016/j.ejmech.2019.112007] [PMID: 31881489]
[24]
Su, D.S.; Qu, J.; Schulz, M.; Blackledge, C.W.; Yu, H.; Zeng, J.; Burgess, J.; Reif, A.; Stern, M.; Nagarajan, R.; Pappalardi, M.B.; Wong, K.; Graves, A.P.; Bonnette, W.; Wang, L.; Elkins, P.; Knapp-Reed, B.; Carson, J.D.; McHugh, C.; Mohammad, H.; Kruger, R.; Luengo, J.; Heerding, D.A.; Creasy, C.L. Discovery of isoxazole amides as potent and selective SMYD3 inhibitors. ACS Med. Chem. Lett., 2019, 11(2), 133-140.
[http://dx.doi.org/10.1021/acsmedchemlett.9b00493] [PMID: 32071679]
[http://dx.doi.org/10.1021/acsmedchemlett.9b00493] [PMID: 32071679]
[25]
Kumar, A.; Maurya, R.A.; Sharma, S.; Ahmad, P.; Singh, A.B.; Tamrakar, A.K.; Srivastava, A.K. Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents. Bioorg. Med. Chem., 2009, 17(14), 5285-5292.
[http://dx.doi.org/10.1016/j.bmc.2009.05.033] [PMID: 19500993]
[http://dx.doi.org/10.1016/j.bmc.2009.05.033] [PMID: 19500993]
[26]
Nie, J.P.; Qu, Z.N.; Chen, Y.; Chen, J.H.; Jiang, Y.; Jin, M.N.; Yu, Y.; Niu, W.Y.; Duan, H.Q.; Qin, N. Discovery and anti-diabetic effects of novel isoxazole based flavonoid derivatives. Fitoterapia, 2020, 142, 104499.
[http://dx.doi.org/10.1016/j.fitote.2020.104499] [PMID: 32058049]
[http://dx.doi.org/10.1016/j.fitote.2020.104499] [PMID: 32058049]
[27]
Almasirad, A.; Firoozpour, L.; Nejati, M.; Edraki, N.; Firuzi, O.; Khoshneviszadeh, M.; Mahdavi, M.; Moghimi, S.; Safavi, M.; Shafiee, A.; Foroumadi, A. Design, synthesis, and biological evaluation of new series of 2-amido-1,3,4-thiadiazole derivatives as cytotoxic agents. Z. Z. Naturforsch. B, 2016, 71, 205-210.
[http://dx.doi.org/10.1515/znb-2015-0138]
[http://dx.doi.org/10.1515/znb-2015-0138]
[28]
Saeedi, M.; Mohammadi-Khanaposhtani, M.; Pourrabia, P.; Razzaghi, N.; Ghadimi, R.; Imanparast, S.; Faramarzi, M.A.; Bandarian, F.; Esfahani, E.N.; Safavi, M.; Rastegar, H.; Larijani, B.; Mahdavi, M.; Akbarzadeh, T. Design and synthesis of novel quinazolinone-1,2,3-triazole hybrids as new anti-diabetic agents: In vitro α-glucosidase inhibition, kinetic, and docking study. Bioorg. Chem., 2019, 83, 161-169.
[http://dx.doi.org/10.1016/j.bioorg.2018.10.023] [PMID: 30366316]
[http://dx.doi.org/10.1016/j.bioorg.2018.10.023] [PMID: 30366316]
[29]
Zhang, L.; Xu, Q.; Zhu, J.; Xia, G.; Zang, H. Synthesis, α-Glucosidase inhibition and molecular docking studies of tyrosol derivatives. Nat. Prod. Res., 2019, 1-9.
[http://dx.doi.org/10.1080/14786419.2019.1628750] [PMID: 31204495]
[http://dx.doi.org/10.1080/14786419.2019.1628750] [PMID: 31204495]
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