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Letters in Drug Design & Discovery

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

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Research Article

An Ultrasound-assisted Three Component Protocol for the Regio and Stereo-selective Synthesis of Some Novel Dispiroheterocycles and Their Biological Evaluation as Anti-inflammatory, Anti-obesity Agents

Author(s): Sanjeev Kumar, Bhavna Saroha, Ekta Lathwal, Gourav Kumar, Suresh Kumar*, Ramesh Kumar, Priyanka Arya and Neera Raghav

Volume 21, Issue 1, 2024

Published on: 10 April, 2023

Page: [133 - 142] Pages: 10

DOI: 10.2174/1570180820666230306115855

Price: $65

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Abstract

Background: The increasing utilization of spiro compounds in drug discovery, led us to design and synthesize regioselectively some novel dispiroheterocycles, by a standard 1,3-dipolar cycloaddition reaction between 6-hydroxyaurone and in situ generated azomethine ylides, using ultra-sonication as green energy source. These results are first of its kind in the literature reported so far for the similar conditions. After confirmation of the proposed structures spectroscopically, using 1H NMR, 13C NMR and FT-IR spectral data, all the compounds are screened for their potential biological activities.

Methods: Three component protocol, that contain (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one, sarcosine and unsubstituted isatin. In which azomethine ylides react with olefinic dipolarophiles through 1,3-dipolar cycloaddition, which is highly regio- and stero-selective way in situ. Structures of the proposed products have been confirmed using 1H NMR, 13C NMR and FT-IR spectral data.

Results: In order to screen the potential biological activities of the synthesized compounds, their effect was observed on trypsin, amylase and lipase activities. Differential effect has been observed. Trypsin was substantially activated whereas an inhibitory effect was observed for amylase and lipase supported by in silico studies.

Conclusion: Synthesis of six novel 6-hydroxy-1'-methyl-4'-phenyl-3H-dispiro[benzofuran-2,3'- pyrrolidine-2',3''-indoline]-2'',3-dione derivatives have been made using a multicomponent greener protocol. These synthesized compounds have exhibited differential effects toward trypsin, amylase and lipase well supported by in silico studies. Thus, the present study highlights their potential use as antiinflammatory and anti-obesity agents.

Keywords: Aurones, spiro compounds, three-component reaction, dipolar cycloaddition reaction, azomethine ylides, spirooxindole, trypsin, amylase, lipase.

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[1]
Candeias, N.R.; Montalbano, F.; Cal, P.M.S.D.; Gois, P.M.P. Boronic acids and esters in the Petasis-borono Mannich multicomponent reaction. Chem. Rev., 2010, 110(10), 6169-6193.
[http://dx.doi.org/10.1021/cr100108k] [PMID: 20677749]
[2]
Isambert, N.; Duque, M.M.S.; Plaquevent, J.C.; Génisson, Y.; Rodriguez, J.; Constantieux, T. Multicomponent reactions and ionic liquids: A perfect synergy for eco-compatible heterocyclic synthesis. Chem. Soc. Rev., 2011, 40(3), 1347-1357.
[http://dx.doi.org/10.1039/C0CS00013B] [PMID: 20963207]
[3]
Dömling, A.; Wang, W.; Wang, K. Chemistry and biology of multicomponent reactions. Chem. Rev., 2012, 112(6), 3083-3135.
[http://dx.doi.org/10.1021/cr100233r] [PMID: 22435608]
[4]
Brauch, S.; van Berkel, S.S.; Westermann, B. Higher-order multicomponent reactions: Beyond four reactants. Chem. Soc. Rev., 2013, 42(12), 4948-4962.
[http://dx.doi.org/10.1039/c3cs35505e] [PMID: 23426583]
[5]
Shanmugam, P.; Viswambharan, B.; Madhavan, S. Synthesis of novel functionalized 3-spiropyrrolizidine and 3-spiropyrrolidine oxindoles from Baylis-Hillman adducts of isatin and heteroaldehydes with azomethine ylides via [3+2]-cycloaddition. Org. Lett., 2007, 9(21), 4095-4098.
[http://dx.doi.org/10.1021/ol701533d] [PMID: 17877359]
[6]
Zhang, M.; Yang, W.; Li, K.; Sun, K.; Ding, J.; Yang, L.; Zhu, C. Facile synthesis of dispiroheterocycles through one-pot [3+ 2] cycloaddition, and their antiviral activity. Synthesis, 2019, 51(20), 3847-3858.
[http://dx.doi.org/10.1055/s-0037-1611900]
[7]
Haddad, S.; Boudriga, S.; Porzio, F.; Soldera, A.; Askri, M.; Knorr, M.; Rousselin, Y.; Kubicki, M.M.; Golz, C.; Strohmann, C. Regio- and stereoselective synthesis of spiropyrrolizidines and piperazines through azomethine ylide cycloaddition reaction. J. Org. Chem., 2015, 80(18), 9064-9075.
[http://dx.doi.org/10.1021/acs.joc.5b01399] [PMID: 26291879]
[8]
Wang, Y.C.; Wang, J.L.; Burgess, K.S.; Zhang, J.W.; Zheng, Q.M.; Pu, Y.D.; Yan, L.J.; Chen, X.B. Green synthesis of new pyrrolidine-fused spirooxindoles via three-component domino reaction in EtOH/H2O. RSC Adv., 2018, 8(11), 5702-5713.
[http://dx.doi.org/10.1039/C7RA13207G] [PMID: 35539589]
[9]
Yu, B.; Yu, D.Q.; Liu, H.M. Spirooxindoles: Promising scaffolds for anticancer agents. Eur. J. Med. Chem., 2015, 97, 673-698.
[http://dx.doi.org/10.1016/j.ejmech.2014.06.056] [PMID: 24994707]
[10]
Kumar, R.S.; Almansour, A.I.; Arumugam, N.; Soliman, S.M.; Kumar, R.R.; Altaf, M.; Ghabbour, H.A.; Krishnamoorthy, B.S. Stereoselective green synthesis and molecular structures of highly functionalized spirooxindole-pyrrolidine hybrids – A combined experimental and theoretical investigation. J. Mol. Struct., 2018, 1152, 266-275.
[http://dx.doi.org/10.1016/j.molstruc.2017.09.073]
[11]
James, M.N.G.; Williams, G.J.B. The molecular and crystal structure of an oxindole alkaloid (6-Hydroxy-2 ′ -(2-methylpropyl)-3,3 ′ -spirotetrahydropyrrolidino-oxindole). Can. J. Chem., 1972, 50(15), 2407-2412.
[http://dx.doi.org/10.1139/v72-386]
[12]
Arun, Y.; Saranraj, K.; Balachandran, C.; Perumal, P.T. Novel spirooxindole–pyrrolidine compounds: Synthesis, anticancer and molecular docking studies. Eur. J. Med. Chem., 2014, 74, 50-64.
[http://dx.doi.org/10.1016/j.ejmech.2013.12.027] [PMID: 24445312]
[13]
Jossang, A.; Jossang, P.; Hadi, H.A.; Sevenet, T.; Bodo, B. Horsfiline, an oxindole alkaloid from Horsfieldia superba. J. Org. Chem., 1991, 56(23), 6527-6530.
[http://dx.doi.org/10.1021/jo00023a016]
[14]
Jones, K.; Wilkinson, J. A total synthesis of horsfiline via aryl radical cyclisation. J. Chem. Soc. Chem. Commun., 1992, 1767-1769(24), 1767.
[http://dx.doi.org/10.1039/c39920001767]
[15]
Laronze, J-Y.; Bascop, S-I.; Sapi, J.; Levy, J. On the synthesis of the oxindole alkaloid:(±)-Horsfiline. Heterocycles, 1994, 38(4), 725-732.
[http://dx.doi.org/10.3987/COM-93-6639]
[16]
García Prado, E.; García Gimenez, M.D.; De la Puerta Vázquez, R.; Espartero Sánchez, J.L.; Sáenz Rodríguez, M.T. Antiproliferative effects of mitraphylline, a pentacyclic oxindole alkaloid of Uncaria tomentosa on human glioma and neuroblastoma cell lines. Phytomedicine, 2007, 14(4), 280-284.
[http://dx.doi.org/10.1016/j.phymed.2006.12.023] [PMID: 17296291]
[17]
Cui, C.B.; Kakeya, H.; Osada, H. Spirotryprostatin B, a novel mammalian cell cycle inhibitor produced by Aspergillus fumigatus. J. Antibiot. (Tokyo), 1996, 49(8), 832-835.
[http://dx.doi.org/10.7164/antibiotics.49.832] [PMID: 8823522]
[18]
Cui, C.B.; Kakeya, H.; Osada, H. Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron, 1996, 52(39), 12651-12666.
[http://dx.doi.org/10.1016/0040-4020(96)00737-5]
[19]
Bhaskar, G.; Arun, Y.; Balachandran, C.; Saikumar, C.; Perumal, P.T. Synthesis of novel spirooxindole derivatives by one pot multicomponent reaction and their antimicrobial activity. Eur. J. Med. Chem., 2012, 51, 79-91.
[http://dx.doi.org/10.1016/j.ejmech.2012.02.024] [PMID: 22405285]
[20]
Sebahar, P.R.; Williams, R.M. The Asymmetric Total Synthesis of (+)- and (−)-Spirotryprostatin B. J. Am. Chem. Soc., 2000, 122(23), 5666-5667.
[http://dx.doi.org/10.1021/ja001133n]
[21]
Chandran, R.; Prabhakaran, S.M.; Kumar, V.; Thakar, S.R.; Tiwari, K.N. Approaches towards 3‐Substituted‐3‐hydroxyoxindole and Spirooxindole‐Pyran Derivatives in a reaction of isatin with acetylacetone in aqueous media. Chem. Sel., 2019, 4(43), 12757-12761.
[http://dx.doi.org/10.1002/slct.201903301]
[22]
Raj, A.A.; Raghunathan, R. SrideviKumari, M.R.; Raman, N. Synthesis, antimicrobial and antifungal activity of a new class of spiro pyrrolidines. Bioorg. Med. Chem., 2003, 11(3), 407-419.
[http://dx.doi.org/10.1016/S0968-0896(02)00439-X] [PMID: 12517436]
[23]
Zhang, W.; Go, M.L. Functionalized 3-benzylidene-indolin-2-ones: Inducers of NAD(P)H-quinone oxidoreductase 1 (NQO1) with antiproliferative activity. Bioorg. Med. Chem., 2009, 17(5), 2077-2090.
[http://dx.doi.org/10.1016/j.bmc.2008.12.052] [PMID: 19200740]
[24]
Periyasami, G.; Raghunathan, R.; Surendiran, G.; Mathivanan, N. Regioselective synthesis and antimicrobial screening of novel ketocarbazolodispiropyrrolidine derivatives. Eur. J. Med. Chem., 2009, 44(3), 959-966.
[http://dx.doi.org/10.1016/j.ejmech.2008.07.009] [PMID: 18722036]
[25]
Zhu, G.D.; Gandhi, V.B.; Gong, J.; Luo, Y.; Liu, X.; Shi, Y.; Guan, R.; Magnone, S.R.; Klinghofer, V.; Johnson, E.F.; Bouska, J.; Shoemaker, A.; Oleksijew, A.; Jarvis, K.; Park, C.; Jong, R.D.; Oltersdorf, T.; Li, Q.; Rosenberg, S.H.; Giranda, V.L. Discovery and SAR of oxindole–pyridine-based protein kinase B/Akt inhibitors for treating cancers. Bioorg. Med. Chem. Lett., 2006, 16(13), 3424-3429.
[http://dx.doi.org/10.1016/j.bmcl.2006.04.005] [PMID: 16644221]
[26]
Moghaddam, F.M.; Khodabakhshi, M.R.; Ghahremannejad, Z.; Foroushani, B.K.; Ng, S.W. A one-pot, three-component regiospecific synthesis of dispiropyrrolidines containing a thiophenone ring via 1,3-dipolar cycloaddition reactions of azomethine ylides. Tetrahedron Lett., 2013, 54(20), 2520-2524.
[http://dx.doi.org/10.1016/j.tetlet.2013.03.023]
[27]
Davasaz Rabbani, M.A.; Khalili, B.; Saeidian, H. Novel edaravone-based azo dyes: Efficient synthesis, characterization, antibacterial activity, DFT calculations and comprehensive investigation of the solvent effect on the absorption spectra. RSC Adv., 2020, 10(59), 35729-35739.
[http://dx.doi.org/10.1039/D0RA06934E] [PMID: 35517118]
[28]
Saeidian, H.; Sadighian, H.; Abdoli, M.; Sahandi, M. Versatile and green synthesis, spectroscopic characterizations, crystal structure and DFT calculations of 1,2,3‒triazole‒based sulfonamides. J. Mol. Struct., 2017, 1131, 73-78.
[http://dx.doi.org/10.1016/j.molstruc.2016.11.027]
[29]
Moghaddam, F.M.; Khodabakhshi, M.R.; Aminaee, M. Highly efficient synthesis of pyrimido[4,5-d]pyrimidine-2,4-dione derivatives catalyzed by iodine. Tetrahedron Lett., 2014, 55(34), 4720-4723.
[http://dx.doi.org/10.1016/j.tetlet.2014.07.006]
[30]
Eldehna, W.M. EL-Naggar, D.H.; Hamed, A.R.; Ibrahim, H.S.; Ghabbour, H.A.; Abdel-Aziz, H.A. One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells. J. Enz. Inhib. Med. Chem., 2018, 33(1), 309-318.
[http://dx.doi.org/10.1080/14756366.2017.1417276] [PMID: 29281924]
[31]
Detsi, A.; Majdalani, M.; Kontogiorgis, C.A.; Hadjipavlou-Litina, D.; Kefalas, P. Natural and synthetic 2′-hydroxy-chalcones and aurones: Synthesis, characterization and evaluation of the antioxidant and soybean lipoxygenase inhibitory activity. Bioorg. Med. Chem., 2009, 17(23), 8073-8085.
[http://dx.doi.org/10.1016/j.bmc.2009.10.002] [PMID: 19853459]
[32]
Huang, W.; Liu, M.Z.; Li, Y.; Tan, Y.; Yang, G.F. Design, syntheses, and antitumor activity of novel chromone and aurone derivatives. Bioorg. Med. Chem., 2007, 15(15), 5191-5197.
[http://dx.doi.org/10.1016/j.bmc.2007.05.022] [PMID: 17524655]
[33]
Bandgar, B.P.; Patil, S.A.; Korbad, B.L.; Biradar, S.C.; Nile, S.N.; Khobragade, C.N. Synthesis and biological evaluation of a novel series of 2,2-bisaminomethylated aurone analogues as anti-inflammatory and antimicrobial agents. Eur. J. Med. Chem., 2010, 45(7), 3223-3227.
[http://dx.doi.org/10.1016/j.ejmech.2010.03.045] [PMID: 20430485]
[34]
Carrasco, M.P.; Newton, A.S.; Gonçalves, L.; Góis, A.; Machado, M.; Gut, J.; Nogueira, F.; Hänscheid, T.; Guedes, R.C.; dos Santos, D.J.V.A.; Rosenthal, P.J.; Moreira, R. Probing the aurone scaffold against Plasmodium falciparum: Design, synthesis and antimalarial activity. Eur. J. Med. Chem., 2014, 80, 523-534.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.076] [PMID: 24813880]
[35]
Haudecoeur, R.; Ahmed-Belkacem, A.; Yi, W.; Fortuné, A.; Brillet, R.; Belle, C.; Nicolle, E.; Pallier, C.; Pawlotsky, J.M.; Boumendjel, A. Discovery of naturally occurring aurones that are potent allosteric inhibitors of hepatitis C virus RNA-dependent RNA polymerase. J. Med. Chem., 2011, 54(15), 5395-5402.
[http://dx.doi.org/10.1021/jm200242p] [PMID: 21699179]
[36]
Shin, S.Y.; Shin, M.C.; Shin, J.S.; Lee, K.T.; Lee, Y.S. Synthesis of aurones and their inhibitory effects on nitric oxide and PGE2 productions in LPS-induced RAW 264.7 cells. Bioorg. Med. Chem. Lett., 2011, 21(15), 4520-4523.
[http://dx.doi.org/10.1016/j.bmcl.2011.05.117] [PMID: 21723122]
[37]
Kumar, G.; Lathwal, E.; Saroha, B.; Kumar, S.; Kumar, S.; Chauhan, N.S.; Kumar, T. Synthesis and biological evaluation of quinoline‐based novel aurones. Chem. Sel., 2020, 5(12), 3539-3543.
[http://dx.doi.org/10.1002/slct.201904912]
[38]
Zheng, X.; Wang, H.; Liu, Y.M.; Yao, X.; Tong, M.; Wang, Y.H.; Liao, D.F. Synthesis, characterization, and anticancer effect of trifluoromethylated aurone derivatives. J. Heterocycl. Chem., 2015, 52(1), 296-301.
[http://dx.doi.org/10.1002/jhet.1969]
[39]
Kumar, S.; Lathwal, E.; Kumar, G.; Saroha, B.; Kumar, S.; Mahata, S.; Sahoo, P.K.; Nasare, V.D. Synthesis of pyrazole based novel aurone analogs and their cytotoxic activity against MCF-7 cell line. Chem. Data Collec., 2020, 30, 100559.
[http://dx.doi.org/10.1016/j.cdc.2020.100559]
[40]
Mikheev, I.V.; Pirogova, M.O.; Usoltseva, L.O.; Uzhel, A.S.; Bolotnik, T.A.; Kareev, I.E.; Bubnov, V.P.; Lukonina, N.S.; Volkov, D.S.; Goryunkov, A.A.; Korobov, M.V.; Proskurnin, M.A. Green and rapid preparation of long-term stable aqueous dispersions of fullerenes and endohedral fullerenes: The pros and cons of an ultrasonic probe. Ultrason. Sonochem., 2021, 73, 105533.
[http://dx.doi.org/10.1016/j.ultsonch.2021.105533] [PMID: 33799110]
[41]
Banerjee, B. Recent developments on ultrasound assisted catalyst-free organic synthesis. Ultrason. Sonochem., , 2017, 35(Pt A), 1-14.
[http://dx.doi.org/10.1016/j.ultsonch.2016.09.023] [PMID: 27771266]
[42]
Kiranmye, T.; Vadivelu, M.; Sampath, S.; Muthu, K.; Karthikeyan, K. Ultrasound-assisted catalyst free synthesis of 1,4-/1,5-disubstituted-1,2,3-triazoles in aqueous medium. Sustain. Chem. Pharm., 2021, 19, 100358.
[http://dx.doi.org/10.1016/j.scp.2020.100358]
[43]
Saroha, B.; Kumar, G.; Kumar, S.; Kumari, M.; Rani, M.; Raghav, N.; Sahoo, P.K.; Ghosh, S.; Mahata, S.; Nasare, V.D. Ultrasound assisted a one pot multicomponent and greener synthesis of 1,2,3-triazole incorporated aurone hybrids: Cathepsin B inhibition, anti-cancer activity against AGS cell line, and in silico docking evaluation. Curr. Res. Green Sustain. Chem., 2022, 5, 100295.
[http://dx.doi.org/10.1016/j.crgsc.2022.100295]
[44]
Arya, P.; Raghav, N. In vitro studies of Curcumin-β-cyclodextrin inclusion complex as sustained release system. J. Mol. Struct., 2021, 1228, 129774.
[http://dx.doi.org/10.1016/j.molstruc.2020.129774]
[45]
Migliolo, L.; de Oliveira, A.S.; Santos, E.A.; Franco, O.L.; de Sales, M.P. Structural and mechanistic insights into a novel non-competitive Kunitz trypsin inhibitor from Adenanthera pavonina L. seeds with double activity toward serine- and cysteine-proteinases. J. Mol. Graph. Model., 2010, 29(2), 148-156.
[http://dx.doi.org/10.1016/j.jmgm.2010.05.006] [PMID: 20816329]
[46]
Xie, F.; Zhang, W.; Gong, S.; Gu, X.; Lan, X.; Wu, J.; Wang, Z. Investigating lignin from Canna edulis ker residues induced activation of α-amylase: Kinetics, interaction, and molecular docking. Food Chem., 2019, 271, 62-69.
[http://dx.doi.org/10.1016/j.foodchem.2018.07.153] [PMID: 30236724]
[47]
Habeych, D.I.; Juhl, P.B.; Pleiss, J.; Vanegas, D.; Eggink, G.; Boeriu, C.G. Biocatalytic synthesis of polyesters from sugar-based building blocks using immobilized Candida antarctica lipase B. J. Mol. Catal., B Enzym., 2011, 71(1-2), 1-9.
[http://dx.doi.org/10.1016/j.molcatb.2011.02.015]
[48]
Kumar, S. An improved one-pot and eco-friendly synthesis of aurones under solvent-free conditions. Green Chem. Lett. Rev., 2014, 7(1), 95-99.
[http://dx.doi.org/10.1080/17518253.2014.895867]
[49]
Sindhu, J.; Singh, H.; Khurana, J.M. A green, multicomponent, regio- and stereo-selective 1,3-dipolar cycloaddition of azides and azomethine ylides generated in situ with bifunctional dipolarophiles using PEG-400. Mol. Divers., 2014, 18(2), 345-355.
[http://dx.doi.org/10.1007/s11030-014-9505-y] [PMID: 24577732]
[50]
Esmaeeli, Z.; Khodabakhshi, M.R.; Mirjafary, Z.; Saeidian, H. A robust three-component synthesis of dispiroheterocycles containing aurone scaffold via 1,3-dipolar cycloaddition reaction of azomethine ylides: regioselectivity and mechanistic overview using DFT calculations. Struct. Chem., 2022, 33(1), 147-157.
[http://dx.doi.org/10.1007/s11224-021-01830-x]
[51]
Seligman, B. Trypsin: An anti-inflammatory agent. Angiology, 1955, 6(3), 208-211.
[http://dx.doi.org/10.1177/000331975500600303] [PMID: 13275725]

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