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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

Novel Pyrazolo[4, 3-c]Quinolin-3-One Derivatives as PDE5A Inhibitors

Author(s): Althaf Shaik, Harshit K. Agarwal, Rashmi Bhakuni and Sivapriya Kirubakaran*

Volume 19, Issue 4, 2019

Page: [305 - 315] Pages: 11

DOI: 10.2174/1568026619666190208164402

Price: $65

Abstract

Background: PDE5A is a phosphodiesterase which specifically hydrolyzes the cGMP to GMP. It takes part in several physiological and pathological pathways and is considered an important drug target. Currently, PDE5 inhibitors (ex; Sildenafil, Tadalafil) available in the market are not only being used for the treatment of erectile dysfunction but at the same time, they are also in clinical trials being investigated as anticancer agents.

Materials & Methods: In this work, we have examined pyrazolo [4,3-c]quinolin-3-ones as PDE5A inhibitors. Pyrazolo [4,3-c]quinolin-3-ones are the class of tricyclic heterocyclic derivatives having a variety of therapeutically interesting drug candidates known for their anti-inflammatory, anti-viral, anti-anxiety and anti-cancer activity. Therefore, synthetic methods providing access to pyrazolo [4, 3-c] quinolin-3-ones are immensely valuable. Here, we are reporting a simple but efficient route for the synthesis of novel 8–morpholino-2-aryl – 2, 5-dihydro-3H-pyrazolo [4, 3-c] quinolin-3-one derivatives.

Results: Further, molecular docking studies of synthesized compounds with human PDE5A protein showed that all the compounds exhibited good docking score in comparison with known inhibitors. In addition, all the synthesized molecules were evaluated against HCT116 cell lines for their antitumor activity.

Conclusion: Among all the synthesized compounds, compound 5a, 5d, and 6e showed better cytotoxicity. Thus, these derivatives can be studied as potential inhibitors of PDE5A.

Keywords: Phosphodiesterase, Pyrazoles, Cytotoxicity, Docking, PDE5A Inhibitors, GMP.

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[1]
Rybalkin, S.D.; Yan, C.; Bornfeldt, K.E.; Beavo, J.A. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ. Res., 2003, 93(4), 280-291.
[http://dx.doi.org/10.1161/01.RES.0000087541.15600.2B] [PMID: 12933699]
[2]
Rotella, D.P. Phosphodiesterase 5 inhibitors: current status and potential applications. Nat. Rev. Drug Discov., 2002, 1(9), 674-682.
[http://dx.doi.org/10.1038/nrd893] [PMID: 12209148]
[3]
Sung, B.J.; Hwang, K.Y.; Jeon, Y.H.; Lee, J.I.; Heo, Y.S.; Kim, J.H.; Moon, J.; Yoon, J.M.; Hyun, Y.L.; Kim, E.; Eum, S.J.; Park, S.Y.; Lee, J.O.; Lee, T.G.; Ro, S.; Cho, J.M. Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature, 2003, 425(6953), 98-102.
[http://dx.doi.org/ 10.1038/nature01914] [PMID: 12955149]
[4]
Barone, I.; Giordano, C.; Bonofiglio, D.; Andò, S.; Catalano, S. Phosphodiesterase type 5 and cancers: progress and challenges. Oncotarget, 2017, 8(58), 99179-99202.
[http://dx.doi.org/ 10.18632/oncotarget.21837] [PMID: 29228762]
[5]
Terrett, N.K.; Bell, A.S.; Brown, D.; Ellis, P. Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg. Med. Chem. Lett., 1996, 6(15), 1819-1824.
[http://dx.doi.org/10.1016/0960-894X(96)00323-X]
[6]
Michael, J.P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep., 2008, 25(1), 166-187.
[http://dx.doi.org/ 10.1039/B612168N] [PMID: 18250901]
[7]
Carotti, A.; Altomare, C.; Savini, L.; Chiasserini, L.; Pellerano, C.; Mascia, M.P.; Maciocco, E.; Busonero, F.; Mameli, M.; Biggio, G.; Sanna, E. High affinity central benzodiazepine receptor ligands. Part 3: insights into the pharmacophore and pattern recognition study of intrinsic activities of pyrazolo[4,3-c]quinolin-3-ones. Bioorg. Med. Chem., 2003, 11(23), 5259-5272.
[http://dx.doi.org/ 10.1016/S0968-0896(03)00527-3] [PMID: 14604690]
[8]
Ferreira, V.F.; Leal, K.Z.; Lindgren, E.B.; de Oliveira, M.R.P.; de Souza, M.C.B.V.; Vasconcelos, T.R.A.; Wardell, J.L.; Wardell, S.M.S.V.; Yoneda, J.D. Structural evaluation of three 2-phenylpyrazolo[4,3-c]quinolin-3-one monohydrates. J. Mol. Struct., 2013, 1051, 299-309.
[http://dx.doi.org/10.1016/j.molstruc.2013.08.032]
[9]
Bourrain, S.; Bryant, H.J.; Macleod, A.M.; Showell, G.A. Aryl-substituted pyrazoloquinolinone derivatives as gaba alpha 5 receptor inverse agonists February 11, 1999.
[10]
Savini, L.; Massarelli, P.; Nencini, C.; Pellerano, C.; Biggio, G.; Maciocco, A.; Tuligi, G.; Carrieri, A.; Cinone, N.; Carotti, A. High affinity central benzodiazepine receptor ligands: synthesis and structure-activity relationship studies of a new series of pyrazolo[4,3-c]quinolin-3-ones. Bioorg. Med. Chem., 1998, 6(4), 389-399.
[http://dx.doi.org/10.1016/S0968-0896(97)10039-6] [PMID: 9597183]
[11]
Fryer, R.I.; Zhang, P.; Rios, R.; Gu, Z.Q.; Basile, A.S.; Skolnick, P. Structure-activity relationship studies at the benzodiazepine receptor (BZR): a comparison of the substitutent effects of pyrazoloquinolinone analogs. J. Med. Chem., 1993, 36(11), 1669-1673.
[http://dx.doi.org/10.1021/jm00063a017] [PMID: 8388472]
[12]
Crespo, M.I.; Gràcia, J.; Puig, C.; Vega, A.; Bou, J.; Beleta, J.; Doménech, T.; Ryder, H.; Segarra, V.; Palacios, J.M. Synthesis and biological evaluation of 2,5-dihydropyrazol. Bioorg. Med. Chem. Lett., 2000, 10(23), 2661-2664.
[http://dx.doi.org/10.1016/S0960-894X(00)00548-5] [PMID: 11128646]
[13]
Mekheimer, R.A.; Ahmed, E.A.; Sadek, K.U. Recent developments in the chemistry of pyrazolo[4,3-c]quinolines. Tetrahedron, 2012, 68(6), 1637-1667.
[http://dx.doi.org/10.1016/j.tet.2011.10.088]
[14]
Wentland, M.P.; Aldous, S.C.; Gruett, M.D.; Perni, R.B.; Powles, R.G.; Danz, D.W.; Klingbeil, K.M.; Peverly, A.D.; Robinson, R.G.; Corbett, T.H.; Rake, J.B.; Coughlin, S.A. The antitumor activity of novel pyrazoloquinoline derivatives. Bioorg. Med. Chem. Lett., 1995, 5(4), 405-410.
[http://dx.doi.org/10.1016/0960-894X(95)-00044-T]
[15]
Stein, R.G.; Biel, J.H.; Singh, T. Antimalarials. 4-Substituted 1H-pyrazolo[3,4-b]quinolines. J. Med. Chem., 1970, 13(1), 153-155.
[http://dx.doi.org/10.1021/jm00295a049] [PMID: 5412098]
[16]
Ghotekar, B. K.; Ghagare, M. G.; Toche, R. B.; Jachak, M. N. Synthesis of new quinoline fused heterocycles such as ben-zo[h]- 1,6-naphthyridines and pyrazolo[4,3-c]quinolines. Monatshefte für Chemie - Chemical Monthly, 2010, 141(2), 169-175.
[17]
Carotti, A.; Altomare, C.; Savini, L.; Chiasserini, L.; Pellerano, C.; Mascia, M.P.; Maciocco, E.; Busonero, F.; Mameli, M.; Biggio, G.; Sanna, E. High affinity central benzodiazepine receptor ligands. Part 3: insights into the pharmacophore and pattern recognition study of intrinsic activities of pyrazolo[4,3-c]quinolin-3-ones. Bioorg. Med. Chem., 2003, 11(23), 5259-5272.
[http://dx.doi.org/ 10.1016/S0968-0896(03)00527-3] [PMID: 14604690]
[18]
Ismaïli, L.; Refouvelet, B.; Robert, J.F. Synthesis of new pyrazolo[4,3-c]quinolin-3-one derivatives and some oxazolo[4,5-c]quinoline-2,4-diones. J. Heterocycl. Chem., 1999, 36(3), 719-722.
[http://dx.doi.org/10.1002/jhet.5570360323]
[19]
Bhupathi, S. Microwave assisted solvent-free synthesis of pyrazolo [4,3-c] quinolines using montmorillonite k-10 clay: an environmental benign approach mikrowellenunterst¨1tzten l semittelfreie syn-thesis von pyrazolo [4,3-c] chinoline verwendung Montmoril-lonit K-10 Clay: An umwelt gutartige ansatz. Heterocyclic Letters, 2013, 2(3), 121.
[20]
Yokoyama, N.; Ritter, B.; Neubert, A.D. 2-Arylpyrazolo[4,3-c]quinolin-3-ones: novel agonist, partial agonist, and antagonist of benzodiazepines. J. Med. Chem., 1982, 25(4), 337-339.
[http://dx.doi.org/10.1021/jm00346a002] [PMID: 6121916]
[21]
López Rivilli, M.J.; Moyano, E.L.; Yranzo, G.I. An alternative approach toward 2-aryl-2H-pyrazolo[4,3-c]-quinolin-3-ones by a multistep synthesis. Tetrahedron Lett., 2010, 51(3), 478-481.
[http://dx.doi.org/10.1016/j.tetlet.2009.10.123]
[22]
Tinsley, H.N.; Gary, B.D.; Thaiparambil, J.; Li, N.; Lu, W.; Li, Y.; Maxuitenko, Y.Y.; Keeton, A.B.; Piazza, G.A. Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition. Cancer Prev. Res. (Phila.), 2010, 3(10), 1303-1313.
[http://dx.doi.org/10.1158/1940-6207.CAPR-10-0030] [PMID: 20876730]
[23]
Mei, X.L.; Yang, Y.; Zhang, Y.J.; Li, Y.; Zhao, J.M.; Qiu, J.G.; Zhang, W.J.; Jiang, Q.W.; Xue, Y.Q.; Zheng, D.W.; Chen, Y.; Qin, W.M.; Wei, M.N.; Shi, Z. Sildenafil inhibits the growth of human colorectal cancer in vitro and in vivo. Am. J. Cancer Res., 2015, 5(11), 3311-3324.
[PMID: 26807313]
[24]
Gould, R.G.; Jacobs, W.A. The Synthesis of Certain Substituted Quinolines and 5,6-Benzoquinolines. J. Am. Chem. Soc., 1939, 61(10), 2890-2895.
[http://dx.doi.org/10.1021/ja01265a088]
[25]
Shah, K.J.; Coats, E.A. Design, synthesis, and correlation analysis of 7-substituted 4-hydroxyquinoline-3-carboxylic acids as inhibitors of cellular respiration. J. Med. Chem., 1977, 20(8), 1001-1006.
[http://dx.doi.org/10.1021/jm00218a003] [PMID: 894670]
[26]
Katritzky, A.R.; Rachwal, S.; Rachwal, B. Recent progress in the synthesis of 1,2,3,4,-tetrahydroquinolines. Tetrahedron, 1996, 52(48), 15031-15070.
[http://dx.doi.org/10.1016/S0040-4020(96)-00911-8]

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