Lemon Juice Mediated Synthesis of 3-Substituted Quinazolin-4(3H)-Ones and their Pharmacological Evaluation

Author(s): Malavattu G. Prasad, C. Vijaya Lakshmi, Naresh K. Katari*, Sreekantha B. Jonnalagadda, Manojit Pal*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 16 , 2019

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Graphical Abstract:


Background: Compounds containing the quinazoline-4(3H)-one framework constitute an important class of fused N-heterocycles that are found in more than 200 naturally occurring alkaloids. These compounds also show a diverse range of pharmacological activities including antitumor properties. This prompted us to explore a series of quinazolin-4-(3H)-one derivatives having no substituent at C-2 as potential cytotoxic agents.

Objective: The objective of this study was to synthesize and evaluate 3-substituted quinazolin-4(3H)-one derivatives for their potential cytotoxic properties.

Methods: A convenient method has been developed for the rapid synthesis of this class of compounds under a mild and non-hazardous reaction condition in good yields. The methodology involved a three-component reaction employing isatoic anhydride, amines and glyoxylic acid as reactants in the presence of lemon juice in PEG- 400 at room temperature (25-30ºC) under ultrasound irradiation. All the synthesized compounds were screened via an MTT assay for their potential cytotoxic properties in vitro using the cancerous cell lines e.g. A549, A2780, HepG2, K562, MCF-7 and HCT-116 and a non-cancerous HEK293 cell line.

Results: Several compounds such as 3a, 3b, 3d, 3e and 3f showed promising growth inhibition against these cancer cell lines but no significant effects on HEK293 cell line. The IC50 values of these compounds were comparable to doxorubicin whereas 3f significantly induced apoptosis in MCF-7 cells that also was comparable to doxorubicin.

Conclusion: An ultrasound-assisted MCR facilitated by lemon juice has been developed to synthesize 3- substituted quinazolin-4(3H)-one derivatives that could act as potential anticancer agents.

Keywords: Lemon juice, ultrasound, quinazolin-4(3H)-one derivatives, anticancer, alkaloids, MTT assay.

Tiwary, B.K.; Pradhan, K.; Nanda, A.K.; Chakraborty, R. Implication of Quinazoline-4(3H)-ones in medicinal chemistry: A brief review. J. Chem. Biol. Ther., 2015, 1(1), 104.
Cao, S.L.; Feng, Y.P.; Jiang, Y.Y.; Liu, S.Y.; Ding, G.Y.; Li, R.T. Synthesis and in vitro antitumor activity of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains. Bioorg. Med. Chem. Lett., 2005, 15(7), 1915-1917.
[http://dx.doi.org/10.1016/j.bmcl.2005.01.083] [PMID: 15780632]
Over, B.; Wetzel, S.; Grütter, C.; Nakai, Y.; Renner, S.; Rauh, D.; Waldmann, H. Natural-product-derived fragments for fragment-based ligand discovery. Nat. Chem., 2013, 5(1), 21-28.
[http://dx.doi.org/10.1038/nchem.1506] [PMID: 23247173]
Raffa, D.; Daidone, G.; Maggio, B.; Schillaci, D.; Plescia, F. Synthesis and antiproliferative activity of novel 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives. Arch. Pharm. (Weinheim), 1999, 332(9), 317-320.
[http://dx.doi.org/10.1002/(SICI)1521-4184(19999)332:9<317:AID-ARDP317>3.0.CO;2-R] [PMID: 10520301]
Murugan, V.; Padmavathy, N.P.; Ramasarma, G.V.; Sharma, S.V.; Suresh, B. Synthesis of some quinazolinone derivatives as possible anticancer agent. Indian J. Heterocycl. Chem., 2003, 13, 143-146.
Girija, K.; Selvam, P.; Nagarajan, R. Synthesis anticancer activity of 3-[5-Amino-6-(2,3-dichlorophenyl)-[1,2,4]triazin-3-yl]-6,8-dibromo-2-substituted-3H-quina-zolin-4-one. Asian J. Chem., 2005, 17, 1111-1115.
Schultz, R.M. Potential of p38 MAP kinase inhibitors in the treatment of cancer. Prog. Drug Res., 2003, 60, 59-92.
[http://dx.doi.org/10.1007/978-3-0348-8012-1_2] [PMID: 12790339]
Campbell, R.M.; Anderson, B.D.; Brooks, N.A.; Brooks, H.B.; Chan, E.M.; De Dios, A.; Gilmour, R.; Graff, J.R.; Jambrina, E.; Mader, M.; McCann, D.; Na, S.; Parsons, S.H.; Pratt, S.E.; Shih, C.; Stancato, L.F.; Starling, J.J.; Tate, C.; Velasco, J.A.; Wang, Y.; Ye, X.S. Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity. Mol. Cancer Ther., 2014, 13(2), 364-374.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0513] [PMID: 24356814]
Das, B.; Banerjee, J. Silica-supported sodium hydrogen sulfate and amberlyst-15: Two efficient heterogeneous catalysts for single-step synthesis of 4(3H)-quinazolinones from anthranilic acid, ortho esters, and amines under solvent-free conditions. Chem. Lett., 2004, 33, 960-961.
Jiang, Z.D.; Chen, R.F. Synthesis of 3,4-dihydropyrimidine-2(1H)-thiones and quinazolin-4(3H)-ones over Yb(III)-resin catalyst under solvent-free conditions. Synth. Commun., 2005, 35, 503-509.
Wang, L.M.; Xia, J.J.; Qin, F.; Qian, C.T.; Sun, J. Yb(OTf)3-catalyzed one-pot synthesis of quinazolin-4(3H)-ones from anthranilic acid, amines, and ortho esters (or formic acid) in solvent-free conditions. Synthesis, 2003, 1241-1247.
Khosropour, A.R.; Mohammadpoor-Baltork, I.; Ghorbankhani, H. Bi(TFA)3-[nbp]FeCl4: A new, efficient, and reusable promoter system for the synthesis of 4(3H)-quinazolinone derivatives. Tetrahedron Lett., 2006, 47, 3561-3564.
Narasimhulu, M.; Mahesh, K.C.; Reddy, T.S.; Rajesh, K.; Venkateswarlu, Y. Lanthanum(III) nitrate hexahydrate or p-toluenesulfonic acid-catalyzed one-pot synthesis of 4(3H)-quinazolinones under solvent-free conditions. Tetrahedron Lett., 2006, 47, 4381-4383.
Ighilahriz, K.; Boutemeur, B.; Chami, F.; Rabia, C.; Hamdi, M.; Hamdi, S.M. A microwave-assisted and heteropolyacids-catalysed cyclocondensation reaction for the synthesis of 4(3H)-quinazolinones. Molecules, 2008, 13(4), 779-789.
[http://dx.doi.org/10.3390/molecules13040779] [PMID: 18463579]
Oskooie, H.A.; Baghernezhad, B.; Heravi, M.M. SnCl4.4H2O as an efficient catalyst for the synthesis of 4(3H)-quinazolinone derivatives. Indian J. Heterocycl. Chem., 2007, 17, 95-96.
Chari, M.A.; Mukkanti, D.S.K. Silica gel/FeCl3: An efficient and recyclable heterogenous catalyst for one-step synthesis of 4(3H)-quinazolinones under solvent-free conditions. Catal. Commun., 2006, 7, 787-790.
Wang, M.; Song, Z.; Zhang, T. Aluminum nitrate-catalyzed one-pot synthesis of 4(3H)-quinazolinones by a three component coupling of anthranilic acid, amines and ortho esters. Synth. Commun., 2011, 41, 385-391.
Rad-Moghadam, K.; Mamghani, M.; Samavi, L. Convergent one-pot synthesis of 3-substituted quinazolin-4(3H)-ones under solvent-free conditions. Synth. Commun., 2006, 36, 2245-2252.
Rao, K.R.; Mekala, R.; Raghunadh, A.; Meruva, S.B.; Kumar, S.P.; Kalita, D.; Laxminarayana, E.; Prasad, B.; Pal, M. A catalyst-free rapid, practical and general synthesis of 2-substituted quinazolin-4(3H)-ones leading to luotonin B and E, bouchardatine and 8-Norrutaecarpine. RSC Advances, 2015, 5, 61575-61579.
Hollinshead, S.P.; Trudell, M.L.; Skolnick, P.; Cook, J.M. Structural requirements for agonist actions at the benzodiazepine receptor: Studies with analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester. J. Med. Chem., 1990, 33(3), 1062-1069.
[http://dx.doi.org/10.1021/jm00165a028] [PMID: 1968513]
Sharma, A.; Li, H-Y. A regioselective and high-yielding method for formaldehyde inclusion in the 3CC Groebke-Blackburn-Bienayme reaction: One-step access to 3-aminoimidazoazines. Synlett, 2011, 10, 1407-1412.
Castellano, S.; Taliani, S.; Milite, C.; Pugliesi, I.; Da Pozzo, E.; Rizzetto, E.; Bendinelli, S.; Costa, B.; Cosconati, S.; Greco, G.; Novellino, E.; Sbardella, G.; Stefancich, G.; Martini, C.; Da Settimo, F. Synthesis and biological evaluation of 4-phenylquinazoline-2-carboxamides designed as a novel class of potent ligands of the translocator protein. J. Med. Chem., 2012, 55(9), 4506-4510.
[http://dx.doi.org/10.1021/jm201703k] [PMID: 22489952]
Lee, Y-J.; Han, Y-R.; Park, W.; Nam, S-H.; Oh, K-B.; Lee, H-S. Synthetic analogs of indole-containing natural products as inhibitors of sortase A and isocitrate lyase. Bioorg. Med. Chem. Lett., 2010, 20(23), 6882-6885.
[http://dx.doi.org/10.1016/j.bmcl.2010.10.029] [PMID: 21035332]
Schumacher, R.W.; Davidson, B.S. Synthesis of didemnolines A-D, N9-substituted β-carboline alkaloids from the marine ascidian Didemnum sp. Tetrahedron, 1999, 55, 935-942.
Trujillo, J.I.; Meyers, M.J.; Anderson, D.R.; Hegde, S.; Mahoney, M.W.; Vernier, W.F.; Buchler, I.P.; Wu, K.K.; Yang, S.; Hartmann, S.J.; Reitz, D.B. Novel tetrahydro-beta-carboline-1-carboxylic acids as inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg. Med. Chem. Lett., 2007, 17(16), 4657-4663.
[http://dx.doi.org/10.1016/j.bmcl.2007.05.070] [PMID: 17570666]
Xin, B.; Tang, W.; Wang, Y.; Lin, G.; Liu, H.; Jiao, Y.; Zhu, Y.; Yuan, H.; Chen, Y.; Lu, T. Design, synthesis and biological evaluation of β-carboline derivatives as novel inhibitors targeting B-Raf kinase. Bioorg. Med. Chem. Lett., 2012, 22(14), 4783-4786.
[http://dx.doi.org/10.1016/j.bmcl.2012.05.053] [PMID: 22704238]
Madrigal, A.; Grande, M.; Avendano, C. The fate of the tryptophan stereocenter in the synthesis of 7,10,16,16a-tetrahydro-11H-quinazolino[2′,3′:3,4]pyrazino[1,2-b]β-carboline-5,8-diones. Tetrahedron Asymmetry, 2000, 11, 3515-3526.
Pal, R. Fruit juice: A natural, green and biocatalyst system in organic synthesis. Open J. Org. Chem., 2013, 1, 47-56.
Deshmukh, M.B.; Patil, S.S.; Jadhav, S.D.; Pawar, P.B. Green approach for Knoevenagel condensation of aromatic aldehydes. Synth. Commun., 2012, 42, 1177-1183.
Patil, S.; Jadhav, S.D.; Deshmuk, M.B. Natural acid catalyzed multi-component reactions as a green approach. Arch. Appl. Sci. Res., 2011, 3, 203-208.
Patil, S.; Jhadav, S.D.; Patil, U.P. Natural acid catalyzed synthesis of schiff base under solvent-free condition: As a green approach. Arch. Appl. Sci. Res., 2012, 4, 1074-1078.
Sachdeva, H.; Saroj, R.; Khaturia, S.; Dwivedi, D. Environ-economic synthesis and characterization of some new 1,2,4-triazole derivatives as organic fluorescent materials and potent fungicidal agents. Org. Chem. Int., 2013, 2013659107
Kumar, S.K.; Rambabu, D.; Kumar, C.H.V.; Sreenivas, B.Y.; Prasad, K.R.S.; Rao, M.V.B.; Pal, M. Catalysis by Amberlyst-15 under ultrasound in water: A green synthesis of 1,2,4-benzothiadiazine-1,1-dioxides and their spiro derivatives. RSC Advances, 2013, 3, 24863-24867.
Nelson, C.E. Lemon juice composition. US2215334A, 1938.
Sharma, P.; Rashmi, S.; Kumar, G.V. Rapid synthesis of amides from ketoximes using citric acid monohydrate over TBAB under green chemistry conditions. J. Adv. Chem. Sci., 2016, 2, 180-182.
Xie, L-Y.; Li, Y-J.; Qu, J.; Duan, Y.; Hu, J.; Liu, K-J.; Cao, Z.; He, W-M. A base-free, ultrasound accelerated one-pot synthesis of 2-sulfonylquinolines in water. Green Chem., 2017, 19, 5642-5646.
Wu, C.; Lu, L-H.; Peng, A-Z.; Jia, G-K.; Peng, C.; Cao, Z.; Tang, Z.; He, W-M.; Xu, X. Ultrasound-promoted brønsted acid ionic liquid-catalyzed hydrothiocyanation of activated alkynes under minimal solvent conditions. Green Chem., 2018, 20, 3683-3688.
Mason, T.J.; Peters, D. Practical Sonochemistry; Woodhead Publishing: Cambridge, United Kingdom, 1991.
Mason, T.J. Sonochemistry and the environment - providing a “green” link between chemistry, physics and engineering. Ultrason. Sonochem., 2007, 14(4), 476-483.
[http://dx.doi.org/10.1016/j.ultsonch.2006.10.008] [PMID: 17207652]
Schiller, J.H.; Gandara, D.R.; Goss, G.D.; Vokes, E.E. Non-small-cell lung cancer: Then and now. J. Clin. Oncol., 2013, 31(8), 981-983.
[http://dx.doi.org/10.1200/JCO.2012.47.5772] [PMID: 23401450]
Pollack, S.J.; Beyer, K.S.; Lock, C.; Müller, I.; Sheppard, D.; Lipkin, M.; Hardick, D.; Blurton, P.; Leonard, P.M.; Hubbard, P.A.; Todd, D.; Richardson, C.M.; Ahrens, T.; Baader, M.; Hafenbradl, D.O.; Hilyard, K.; Bürli, R.W. A comparative study of fragment screening methods on the p38α kinase: New methods, new insights. J. Comput. Aided Mol. Des., 2011, 25(7), 677-687.
[http://dx.doi.org/10.1007/s10822-011-9454-9] [PMID: 21732248]

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Year: 2019
Published on: 23 January, 2020
Page: [2001 - 2009]
Pages: 9
DOI: 10.2174/1871520619666190723151909
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