Synthesis of Piperidine Conjugated Dihydroquinazolin-4(1H)-ones and their Antiproliferative Activity, Molecular Docking Studies and DFT Calculations

Author(s): Kereyagalahally Honneshappa Narasimhamurthy, Chandra, Toreshettahally Ramesh Swaroop, Swamy Jagadish, Kanchugarakoppal Subbegowda Rangappa*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 1 , 2020

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Abstract:

Background: Xanthatin, fluoropyrimidine and thienopyrimidine, pyrazolopyrimidine, pyrimidine carboxamides, and SKLB1002 are reported as VEGFR2 tyrosine kinase inhibitors. Recently, many studies related to different heterocycles conjugated with dihydroquinazolinones are known to have very good biological activities. In this study, we are intended to explore the cytotoxic studies of piperidine conjugated dihydroquinazolinones against colorectal/colon cancer cell lines and along with molecular docking studies and DFT calculations.

Methods: The colorectal/colon cell lines HCT116 and A549 cell lines were treated with these compounds and cytotoxic activities were evaluated by MTT dye uptake method. We performed molecular modelling for compound 3d using the Auto Dock software. The binding of compound 3d with target proteins was studied with the collection of experimentally determined PDB database. Optimized geometry by DFT calculations was performed with B3LYP/6-31G (d) basis set.

Results: Piperidine-conjugated dihydroquinazolinone analogues displayed anticancer activity. Particularly, the compound 3d with electron-withdrawing substituents on a phenyl ring showed significant cytotoxicity against HCT116 and A549 cell lines. Molecular docking studies proved that the compound 3d has good fitting by forming hydrogen bonds with amino acid residues at the active sites of VEGFR2. The HOMO, LUMO, their energies and UV visible spectrum were predicted using DFT calculations.

Conclusion: Four piperidine-conjugated dihydroquinazolinones were synthesized and evaluated against colorectal and colon cancer cell lines. Compound 3d significantly inhibited the growth of HCT116 and A549. Molecular docking studies displayed good fitting of compound 3d by forming different H-bonds with the amino acid at the active sites of the VEGFR2 target. Using a theoretical approach, we optimized HOMO and LUMO plots for the compound 3d.

Keywords: Piperidine-conjugated dihydroquinazolinones, cytotoxicity, human colorectal carcinoma, colon adenocarcinoma, VEGFR2 tyrosine kinase inhibitors, DFT.

[1]
(a) Ferrando, C.; Foy, J.M.; Pratt, C.N.F.W.; Purvis, J.R. On the pharmacological actions of a diuretic, fenquizone, with particular reference to its site of action. J. Pharm. Pharmacol., 1981, 33(4), 219-222.
[http://dx.doi.org/10.1111/j.2042-7158.1981.tb13761.x] [PMID: 6115903]
(b) Wang, G-J.; Wu, X-C.; Chen, C-F.; Lin, L-C.; Huang, Y-T.; Shan, J.; Pang, P.K.T. Vasorelaxing action of rutaecarpine: Effects of rutaecarpine on calcium channel activities in vascular endothelial and smooth muscle cells. J. Pharmacol. Exp. Ther., 1999, 289(3), 1237-1244.
[PMID: 10336511]
[2]
Shi, C-S.; Li, J-M.; Chin, C-C.; Kuo, Y-H.; Lee, Y-R.; Huang, Y-C. Evodiamine induces cell growth arrest, apoptosis and suppresses tumorigenesis in human urothelial cell carcinoma cells. Anticancer Res., 2017, 37(3), 1149-1159.
[http://dx.doi.org/10.21873/anticanres.11428] [PMID: 28314276]
[3]
(a) Wang, Z-X.; Xiang, J-C.; Wang, M.; Ma, J-T.; Wu, Y-D.; Wu, A-X. One-pot total synthesis of evodiamine and its analogues through a continuous biscyclization reaction. Org. Lett., 2018, 20(20), 6380-6383.
[http://dx.doi.org/10.1021/acs.orglett.8b02667] [PMID: 30284836]
(b) Rueping, M.; Antonchick, A.P.; Sugiono, E.; Grenader, K. Asymmetric Brønsted acid catalysis: Catalytic enantioselective synthesis of highly biologically active dihydroquinazolinones. Angew. Chem. Int. Ed. Engl., 2009, 48(5), 908-910.
[http://dx.doi.org/10.1002/anie.200804770] [PMID: 19101974]
(c) Narasimhamurthy, K.H.; Chandrappa, S.; Sharath Kumar, K.S.; Harsha, K.B.; Ananda, H.; Rangappa, K.S. Easy access for the synthesis of 2-aryl 2,3-dihydroquinazolin-4(1H)-ones using gem-dibromomethylarenes as synthetic aldehyde equivalent. RSC Advances, 2014, 4(65), 34479-34486.
[http://dx.doi.org/10.1039/C4RA02312A]
[4]
Rajaka, L.; Penumati, N.; Nagaiah, K.Y.P.; Kumar, C.G. Convenient and scalable synthesis of 2,3-dihydroquinazoli4(1H)-one derivatives and their anticancer activities. Synth. Commun., 2015, 45(15), 1893-1901.
[http://dx.doi.org/10.1080/00397911.2015.1046555]
[5]
Yale, H.L.; Kalkstein, M. Substituted 2,3-Dihydro-4(1H)-quinazolinones. A new class of inhibitors of cell multiplication. J. Med. Chem., 1967, 10(3), 334-336.
[http://dx.doi.org/10.1021/jm00315a010] [PMID: 22185126]
[6]
Bonola, G.; Da Re, P.; Magistretti, M.J.; Massarani, E.; Setnikar, I. 1-aminoacyl-2,3-dihydro-4(1H)-quinazolinone derivatives with choleretic and antifibrillatory activity. J. Med. Chem., 1968, 11(6), 1136-1139.
[http://dx.doi.org/10.1021/jm00312a007] [PMID: 5680025]
[7]
Khalil, M.A.; Soliman, R.; Farghaly, A.M.; Bekhit, A.A. Non-steroidal anti-inflammatory agents: Novel pyrazolyl-, 1,2-oxazolyl-, and 1,3-diazinyl derivatives of 4(3H)-quinazolinones. Arch. Pharm. (Weinheim), 1994, 327(1), 27-30.
[http://dx.doi.org/10.1002/ardp.19943270105] [PMID: 8117186]
[8]
Baldazzi, C.; Barbanti, M.; Basaglia, R.; Benelli, A.; Bertolini, A.; Piani, S. A new series of 6-chloro-2,3-dihydro-4(1H)-quinazolinone derivatives as antiemetic and gastrointestinal motility enhancing agents. Arzneimittelforschung, 1996, 46(9), 911-918.
[PMID: 8876941]
[9]
Birch, H.L.; Buckley, G.M.; Davies, N.; Dyke, H.J.; Frost, E.J.; Gilbert, P.J.; Hannah, D.R.; Haughan, A.F.; Madigan, M.J.; Morgan, T.; Pitt, W.R.; Ratcliffe, A.J.; Ray, N.C.; Richard, M.D.; Sharpe, A.; Taylor, A.J.; Whitworth, J.M.; Williams, S.C. Novel 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones as IMPDH inhibitors. Bioorg. Med. Chem. Lett., 2005, 15(23), 5335-5339.
[http://dx.doi.org/10.1016/j.bmcl.2005.06.108] [PMID: 16202581]
[10]
Büyüktimkin, S.; Buschauer, A.; Schunack, W. Quinazolinones. 18. Synthesis and H1/H2-antihistaminic action of omega-[2-aryl-2,3-dihydro-4(1H)-quinazolinone-1-yl]alkyl substituted ureas and cyanoguanidines. Arch. Pharm. (Weinheim), 1991, 324(5), 291-295.
[http://dx.doi.org/10.1002/ardp.19913240507] [PMID: 1679625]
[11]
Iwashita, A.; Tojo, N.; Matsuura, S.; Yamazaki, S.; Kamijo, K.; Ishida, J.; Yamamoto, H.; Hattori, K.; Matsuoka, N.; Mutoh, S. A novel and potent poly(ADP-ribose) polymerase-1 inhibitor, FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), attenuates neuronal damage in in vitro and in vivo models of cerebral ischemia. J. Pharmacol. Exp. Ther., 2004, 310(2), 425-436.
[http://dx.doi.org/10.1124/jpet.104.066944] [PMID: 15075382]
[12]
(a) Roopan, S.M.; Nawaz Khan, F.; Jin, J.S.; Senthil Kumar, R. An efficient one pot–three component cyclocondensation in the synthesis of 2-(2-chloroquinolin-3-yl)-2,3-dihydroquinazolin-4(1H)-ones: Potential antitumor agents. Res. Chem. Intermed., 2011, 37(8), 919-927.
[http://dx.doi.org/10.1007/s11164-011-0301-3]
(b) Kamal, A.; Bharathi, E.V.; Reddy, J.S.; Ramaiah, M.J.; Dastagiri, D.; Reddy, M.K.; Viswanath, A.; Reddy, T.L.; Shaik, T.B.; Pushpavalli, S.N.C.V.L.; Bhadra, M.P. Synthesis and biological evaluation of 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids as anticancer agents. Eur. J. Med. Chem., 2011, 46(2), 691-703.
[http://dx.doi.org/10.1016/j.ejmech.2010.12.004] [PMID: 21194809]
[13]
Narasimhamurthy, K.H.; Ananda, H.; Sharath, K.S.; Rangappa, K.S. Dihydroquinazolinones as potential antiproliferative and tumor inhibiting agents. OMCIJ, 2016, 1(2)555560
[14]
Hunt, J.A.; Kallashi, F.; Ruzek, R.D.; Sinclair, P.J.; Ita, I.; McCormick, S.X.; Pivnichny, J.V.; Hop, C.E.C.A.; Kumar, S.; Wang, Z.; O’Keefe, S.J.; O’Neill, E.A.; Porter, G.; Thompson, J.E.; Woods, A.; Zaller, D.M.; Doherty, J.B. p38 Inhibitors: Piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones. Bioorg. Med. Chem. Lett., 2003, 13(3), 467-470.
[http://dx.doi.org/10.1016/S0960-894X(02)00990-3] [PMID: 12565952]
[15]
Singh, L.R.; Kumar, A.; Upadhyay, A.; Gupta, S.; Palanati, G.R.; Sikka, K.; Siddiqi, M.I.; Yadav, P.N.; Sashidhara, K.V. Discovery of coumarin-dihydroquinazolinone analogs as niacin receptor 1 agonist with in-vivo anti-obesity efficacy. Eur. J. Med. Chem., 2018, 152(25), 208-222.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.037] [PMID: 29709786]
[16]
Selvakumar, B.P.; Elango, K. Synthesis, characterization and in vitro antibacterial evaluation of 1-(7,7-dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)piperidine-4-carboxamide derivatives. Res. Chem. Intermed., 2017, 43, 5535-5546.
[http://dx.doi.org/10.1007/s11164-017-2945-0]
[17]
Jothieswari, D.; Reddy, K.B. Antioxidant activity of some newer dihydro quinazolin-4-one derivatives. IJNTPS, 2015, 5(5), 162-171.
[18]
Piotrowska, D.G.; Andrei, G.; Schols, D.; Snoeck, R.; Grabkowska-Drużyc, M. New isoxazolidine-conjugates of quinazolinones-synthesis, antiviral and cytostatic activity. Molecules, 2016, 21(7), 959.
[http://dx.doi.org/10.3390/molecules21070959] [PMID: 27455228]
[19]
Ismail, M.A.H.; Barker, S.; Abou el-Ella, D.A.; Abouzid, K.A.M.; Toubar, R.A.; Todd, M.H. Design and synthesis of new tetrazolyl- and carboxy-biphenylylmethyl-quinazolin-4-one derivatives as angiotensin II AT1 receptor antagonists. J. Med. Chem., 2006, 49(5), 1526-1535.
[http://dx.doi.org/10.1021/jm050232e] [PMID: 16509571]
[20]
Iqbal, J.; Saeed, A.; Shah, S.J.; al-Rashida, M.; Shams-ul, M. Biological evaluation of azomethine-dihydroquinazolinone conjugates as cancer and cholinesterase inhibitors. Med. Chem., 2016, 12(1), 74-82.
[21]
Basagiannis, D.; Christoforidis, S. Constitutive endocytosis of VEGFR2 protects the receptor against shedding. J. Biol. Chem., 2016, 291(32), 16892-16903.
[http://dx.doi.org/10.1074/jbc.M116.730309] [PMID: 27298320]
[22]
Domingues, I.; Rino, J.; Demmers, J.A.A.; de Lanerolle, P.; Santos, S.C.R. VEGFR2 translocates to the nucleus to regulate its own transcription. PLoS One, 2011, 6(9)e25668
[http://dx.doi.org/10.1371/journal.pone.0025668] [PMID: 21980525]
[23]
Tugues, S.; Koch, S.; Gualandi, L.; Li, X.; Claesson-Welsh, L. Vascular endothelial growth factors and receptors: Anti-angiogenic therapy in the treatment of cancer. Mol. Aspects Med., 2011, 32(2), 88-111.
[http://dx.doi.org/10.1016/j.mam.2011.04.004] [PMID: 21565214]
[24]
Holmes, K.; Roberts, O.L.; Thomas, A.M.; Cross, M.J. Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition. Cell. Signal., 2007, 19(10), 2003-2012.
[http://dx.doi.org/10.1016/j.cellsig.2007.05.013] [PMID: 17658244]
[25]
Gotink, K.J.; Verheul, H.M. Anti-angiogenic tyrosine kinase inhibitors: What is their mechanism of action? Angiogenesis, 2010, 13(1), 1-14.
[http://dx.doi.org/10.1007/s10456-009-9160-6] [PMID: 20012482]
[26]
Bang, Y.J.; Kang, Y.K.; Kang, W.K.; Boku, N.; Chung, H.C.; Chen, J.S.; Doi, T.; Sun, Y.; Shen, L.; Qin, S.; Ng, W.T.; Tursi, J.M.; Lechuga, M.J.; Lu, D.R.; Ruiz-Garcia, A.; Sobrero, A. Phase II study of sunitinib as second-line treatment for advanced gastric cancer. Invest. New Drugs, 2011, 29(6), 1449-1458.
[http://dx.doi.org/10.1007/s10637-010-9438-y] [PMID: 20461441]
[27]
Aziz, M.A.; Serya, R.A.T.; Lasheen, D.S.; Abdel-Aziz, A.K.; Esmat, A.; Mansour, A.M.; Singab, A.N.B.; Abouzid, K.A.M. Discovery of potent VEGFR-2 inhibitors based on furopyrimidine and thienopyrimidne scaffolds as cancer targeting agents. Sci. Rep., 2016, 6, 24460.
[http://dx.doi.org/10.1038/srep24460] [PMID: 27080011]
[28]
Li, H.; Ha, H.L.; Ding, X.; Bae, C.; Gazy, N.; Hao, J.; Zhong, L. DMH4, a VEGFR2 inhibitor, effectively suppresses growth and invasion of lung cancer cells. J. Appl. Biomed., 2018, 16(1), 46-50.
[http://dx.doi.org/10.1016/j.jab.2017.10.006]
[29]
Zhang, L.; Shan, Y.; Ji, X.; Zhu, M.; Li, C.; Sun, Y.; Si, R.; Pan, X.; Wang, J.; Ma, W.; Dai, B.; Wang, B.; Zhang, J. Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents. Oncotarget, 2017, 8(62), 104745-104760.
[http://dx.doi.org/10.18632/oncotarget.20065] [PMID: 29285210]
[30]
Yu, Y.; Yu, J.; Pei, C.G.; Li, Y.Y.; Tu, P.; Gao, G.P.; Shao, Y. Xanthatin, a novel potent inhibitor of VEGFR2 signaling, inhibits angiogenesis and tumor growth in breast cancer cells. Int. J. Clin. Exp. Pathol., 2015, 8(9), 10355-10364.
[PMID: 26617743]
[31]
Zhang, S.; Cao, Z.; Tian, H.; Shen, G.; Ma, Y.; Xie, H.; Liu, Y.; Zhao, C.; Deng, S.; Yang, Y.; Zheng, R.; Li, W.; Zhang, N.; Liu, S.; Wang, W.; Dai, L.; Shi, S.; Cheng, L.; Pan, Y.; Feng, S.; Zhao, X.; Deng, H.; Yang, S.; Wei, Y. SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits angiogenesis and tumor growth in vivo. Clin. Cancer Res., 2011, 17(13), 4439-4450.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-3109] [PMID: 21622720]
[32]
Bold, G.; Schnell, C.; Furet, P.; McSheehy, P.; Brüggen, J.; Mestan, J.; Manley, P.W.; Drückes, P.; Burglin, M.; Dürler, U.; Loretan, J.; Reuter, R.; Wartmann, M.; Theuer, A.; Bauer-Probst, B.; Martiny-Baron, G.; Allegrini, P.; Goepfert, A.; Wood, J.; Littlewood-Evans, A. A novel potent oral series of vegfr2 inhibitors abrogate tumor growth by inhibiting angiogenesis. J. Med. Chem., 2016, 59(1), 132-146.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01582] [PMID: 26629594]
[33]
Chandrappa, S.; Kavitha, C.V.; Shahabuddin, M.S.; Vinaya, K.; Ananda Kumar, C.S.; Ranganatha, S.R.; Raghavan, S.C.; Rangappa, K.S. Synthesis of 2-(5-((5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid derivatives and evaluation of their cytotoxicity and induction of apoptosis in human leukemia cells. Bioorg. Med. Chem., 2009, 17(6), 2576-2584.
[http://dx.doi.org/10.1016/j.bmc.2009.01.016] [PMID: 19243955]
[34]
Raghavendra, G.M.; Nandeesha, K.N.; Sandhya, N.C.; Rangappa, K.S.; Mantelingu, K. Transition metal free one-pot synthesis of quinazolinones and their alkaloids. Int. J. Chem., 2014, 35(2), 1634-1642.
[35]
Han, G.; Tamaki, M.; Hruby, V.J. Fast, efficient and selective deprotection of the tert-butoxycarbonyl (Boc) group using HCl/dioxane (4 m). J. Pept. Res., 2001, 58(4), 338-341.
[http://dx.doi.org/10.1034/j.1399-3011.2001.00935.x] [PMID: 11606219]
[36]
Narasimhamurthy, K.H. Novel approach for the synthesis of nitrogen containing heterocycles and their biological studies. Ph.D Thesis, University of Mysore, . 2015.
[37]
Balaraman, S.; Vaidyanathan, S.P.; Madhuri, S.; Kuppanagounder, P.E. Synthesis and antiviral activity of 4-(7,7-dimethyl-4-[4-N-aroyl/benzyl1-piperazinyl]-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine derivatives. ARKIVOC, 2017, iv, 353-364.
[http://dx.doi.org/10.24820/ark.5550190.p010.037]
[38]
Sharath, K.S.; Hanumappa, A.; Hegde, M.; Narasimhamurthy, K.H.; Raghavan, S.C.; Rangappa, K.S. Synthesis and antiproliferative effect of novel 4-thiazolidinone-, pyridine- and piperazine-based conjugates on human leukemic cells. Eur. J. Med. Chem., 2014, 81(0), 341-349.
[http://dx.doi.org/10.1016/j.ejmech.2014.05.009] [PMID: 24852281]
[39]
Dennington, R.; Keith, T.; and Millam, J. (2009) Gauss View, Version 5; Semichem Inc., Shawnee Mission
[40]
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.P.; Izmaylov, A.F.; Bloino, J.; Zheng, G.; Sonnenberg, J.L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J.A., Jr; Peralta, J.E.; Ogliaro, F.; Bearpark, M.; Heyd, J.J.; Brothers, E.; Kudin, K.N.; Staroverov, V.N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J.C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.M.; Klene, M. J. E.; Knox, Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; and Fox, D. J., (2010) Gaussian 09, Revision B.01. Gaussian Inc., Wallingford.
[41]
Jones, G.; Willett, P.; Glen, R.C.; Leach, A.R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol., 1997, 267(3), 727-748.
[http://dx.doi.org/10.1006/jmbi.1996.0897] [PMID: 9126849]
[42]
Tripathi, A.; Bankaitis, V.A. Molecular docking: From lock and key to combination lock. J Mol Med Clin Appl, 2017, 2(1)
[http://dx.doi.org/10.16966/2575-0305.106] [PMID: 29333532]


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VOLUME: 17
ISSUE: 1
Year: 2020
Page: [85 - 93]
Pages: 9
DOI: 10.2174/1570180816666190613120349

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