Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis and In silico Studies of Quinazolinone Derivatives as PARP-1 Inhibitors

Author(s): Sonia Verma, Akashdeep Singh Pathania, Somesh Baranwal and Pradeep Kumar*

Volume 17, Issue 12, 2020

Page: [1552 - 1565] Pages: 14

DOI: 10.2174/1570180817999200719152959

Price: $65

Abstract

Background: Cancer is a leading cause of deaths worldwide, accounting for 9.6 million deaths in 2018. According to the WHO, the most common causes of cancer deaths are lung, colorectal, stomach liver and breast cancer.

Introduction: PARP-1 has a crucial role in cell proliferation, survival and death due to its role in the regulation of multiple biological processes. Quinazolinone and its derivatives represent a large class of biologically active compounds that exhibit a broad spectrum of biological activities such as anti-HIV, anticancer, antifungal, antibacterial, anticonvulsant, anti-inflammatory, antidepressant, antimalarial, antioxidant and antileishmanial activities.

Methods: In this study, we have synthesized quinazolinone derivatives by reaction of 2- aminobenzamide and substituted benzaldehydes. The synthesized compounds were also screened in silico for their PARP-1 binding affinities by molecular docking studies using Schrodinger 2016 software. In silico ADME studies were also performed for the synthesized compounds by using QikProp tool of Schrodinger software.

Results: Results of in silico studies indicated that quinazolinone derivatives exhibited a good affinity towards the active site of PARP-1. Out of all synthesized compounds, SVA-11 exhibited a maximum dock score (-10.421). Results of ADME studies indicated the suitability of synthesized compounds as drug candidates.

Conclusion: The synthesized compounds showed better docking scores than reference drug valiparib. Furthermore, they exhibited favorable ADME profile. Therefore, they may serve as lead compounds in the discovery of PARP-1 inhibitors.

Keywords: Cancer, PARP-1, quinazolinone, in silico, docking, ADME.

« Previous Next »
Graphical Abstract

[1]
Murtaugh, M.P.; Steer, C.J.; Sreevatsan, S.; Patterson, N.; Kennedy, S.; Sriramarao, P. The science behind One Health: At the interface of humans, animals, and the environment. Ann. N. Y. Acad. Sci., 2017, 1395(1), 12-32.
[http://dx.doi.org/10.1111/nyas.13355] [PMID: 28505393]
[2]
Cotter, M.B.; Loda, M. Introduction to Pathology and Epidemiology of Cancer; Springer, 2017, pp. 27-42.
[http://dx.doi.org/10.1007/978-3-319-35153-7_3]
[3]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[4]
Marín de Mas, I.; Aguilar, E.; Jayaraman, A.; Polat, I.H.; Martín-Bernabé, A.; Bharat, R.; Foguet, C.; Milà, E.; Papp, B.; Centelles, J.J.; Cascante, M. Cancer cell metabolism as new targets for novel designed therapies. Future Med. Chem., 2014, 6(16), 1791-1810.
[http://dx.doi.org/10.4155/fmc.14.119] [PMID: 25574531]
[5]
Laird, P.W. Cancer epigenetics. Hum. Mol. Genet, 2005, 14(Spec No.1), R65-R76.
[http://dx.doi.org/10.1093/hmg/ddi113] [PMID: 15809275]
[6]
https://www.who.int/news-room/fact-sheets/detail/cancer
[7]
Jagtap, P.G.; Baloglu, E.; Southan, G.J.; Mabley, J.G.; Li, H.; Zhou, J.; van Duzer, J.; Salzman, A.L.; Szabó, C. Discovery of potent poly(ADP-ribose) polymerase-1 inhibitors from the modification of indeno[1,2-c]isoquinolinone. J. Med. Chem., 2005, 48(16), 5100-5103.
[http://dx.doi.org/10.1021/jm0502891] [PMID: 16078828]
[8]
Gibson, B.A.; Kraus, W.L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol., 2012, 13(7), 411-424.
[http://dx.doi.org/10.1038/nrm3376] [PMID: 22713970]
[9]
Schiewer, M.J.; Knudsen, K.E. Transcriptional roles of PARP1 in cancer. Mol. Cancer Res., 2014, 12(8), 1069-1080.
[http://dx.doi.org/10.1158/1541-7786.MCR-13-0672] [PMID: 24916104]
[10]
Jafari, E.; Khajouei, M.R.; Hassanzadeh, F.; Hakimelahi, G.H.; Khodarahmi, G.A. Quinazolinone and quinazoline derivatives: Recent structures with potent antimicrobial and cytotoxic activities. Res. Pharm. Sci., 2016, 11(1), 1-14.
[PMID: 27051427]
[11]
Wang, L.; Liang, C.; Li, F.; Guan, D.; Wu, X.; Fu, X.; Lu, A.; Zhang, G. PARP1 in carcinomas and PARP1 inhibitors as antineoplastic drugs. Int. J. Mol. Sci., 2017, 18(10), 2111.
[http://dx.doi.org/10.3390/ijms18102111] [PMID: 28991194]
[12]
Przybycinski, J.; Nalewajska, M.; Marchelek-Mysliwiec, M.; Dziedziejko, V.; Pawlik, A. Poly-ADP-ribose polymerases (PARPs) as a therapeutic target in the treatment of selected cancers. Expert Opin. Ther. Targets, 2019, 23(9), 773-785.
[http://dx.doi.org/10.1080/14728222.2019.1654458]
[13]
Abdel Gawad, N.M.; Georgey, H.H.; Youssef, R.M.; El-Sayed, N.A. Synthesis and antitumor activity of some 2, 3-disubstituted quinazolin-4(3H)-ones and 4, 6- disubstituted- 1, 2, 3, 4-tetrahydroquinazolin-2H-ones. Eur. J. Med. Chem., 2010, 45(12), 6058-6067.
[http://dx.doi.org/10.1016/j.ejmech.2010.10.008] [PMID: 21051122]
[14]
Rana, A.M.; Desai, K.R.; Jauhari, S. Synthesis, characterization, and pharmacological evaluation of 1-[2-(6-nitro-4-oxo-2-phenyl-4H-quinazolin-3-yl)-ethyl]-3-phenyl ureas. Med. Chem. Res., 2013, 22(1), 225-233.
[http://dx.doi.org/10.1007/s00044-012-0004-3]
[15]
Kumar, A.; Sharma, S. Archana; Bajaj, K.; Sharma, S.; Panwar, H.; Singh, T.; Srivastava, V.K. Some new 2,3,6-trisubstituted quinazolinones as potent anti-inflammatory, analgesic and COX-II inhibitors. Bioorg. Med. Chem., 2003, 11(23), 5293-5299.
[http://dx.doi.org/10.1016/S0968-0896(03)00501-7] [PMID: 14604693]
[16]
Kavitha, K.; Srinivasan, N.; Haribabu, Y. a review on quinazolinone andiits derivatives with diverse biological activities. World J. Pharm. Pharm. Sci., 2018, 7(4), 628-649.
[17]
Wang, Z.; Wang, M.; Yao, X.; Li, Y.; Tan, J.; Wang, L.; Qiao, W.; Geng, Y.; Liu, Y.; Wang, Q. Design, synthesis and antiviral activity of novel quinazolinones. Eur. J. Med. Chem., 2012, 53, 275-282.
[http://dx.doi.org/10.1016/j.ejmech.2012.04.010] [PMID: 22546200]
[18]
Hemalatha, K.; Girija, K. Synthesis of some novel 2, 3-disubstituted quinazolinone derivatives as analgesic and anti-inflammatory agents. Int. J. Pharm. Pharm. Sci., 2011, 3(2), 103-106.
[19]
Rajput, R.; Mishra, A.P. A review on biological activity of quinazolinones. Int. J. Pharma Sci., 2012, 4(2), 66-70.
[20]
Darwish, K.; Dakhil, O. A Review on synthesis and biological profiles of some Quinazolines and (4H)-3, 1-Quinazolin-4-ones of active substituents and their uses as starting materials in reaction schemes. Libyan J. Sci. Tech., 2017, 6(1), 8-13.
[21]
Driessche, G.V.D.; Fourches, D. Adverse drug reactions triggered by the common HLA-B57:01 variant: A molecular docking study. J. Cheminform., 2017, 9(13), 1-17.
[22]
Sastry, G.M.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des., 2013, 27(3), 221-234.
[http://dx.doi.org/10.1007/s10822-013-9644-8] [PMID: 23579614]
[23]
Kumar, S.; Singh, J.; Narasimhan, B.; Shah, S.A.A.; Lim, S.M.; Ramasamy, K.; Mani, V. Reverse pharmacophore mapping and molecular docking studies for discovery of GTPase HRas as promising drug target for bis-pyrimidine derivatives. Chem. Cent. J., 2018, 12(1), 106.
[http://dx.doi.org/10.1186/s13065-018-0475-5] [PMID: 30345469]
[24]
Sharma, V.; Sharma, P.C.; Kumar, V. In silico molecular docking analysis of natural pyridoacridines as anticancer agents Adv. Chem, 2016, 1-9.
[http://dx.doi.org/10.1155/2016/5409387]
[25]
Singh, J.; Kumar, M.; Mansuri, R.; Sahoo, G.C.; Deep, A. Inhibitor designing, virtual screening, and docking studies for methyltransferase: A potential target against dengue virus. J. Pharm. Bioallied Sci., 2016, 8(3), 188-194.
[http://dx.doi.org/10.4103/0975-7406.171682] [PMID: 27413346]
[26]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID: 17034125]
[27]
Lenselink, E.B.; Louvel, J.; Forti, A.F.; van Veldhoven, J.P.D.; de Vries, H.; Mulder-Krieger, T.; McRobb, F.M.; Negri, A.; Goose, J.; Abel, R.; van Vlijmen, H.W.T.; Wang, L.; Harder, E.; Sherman, W.; IJzerman, A.P.; Beuming, T. predicting binding affinities for GPCR ligands using free-energy perturbation. ACS Omega, 2016, 1(2), 293-304.
[http://dx.doi.org/10.1021/acsomega.6b00086] [PMID: 30023478]
[28]
Kalra, S.; Joshi, G.; Munshi, A.; Kumar, R. Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors. Eur. J. Med. Chem., 2017, 142, 424-458.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.071] [PMID: 28911822]
[29]
Lee, Y-R.; Yu, D-S.; Liang, Y-C.; Huang, K-F.; Chou, S-J.; Chen, T.C.; Lee, C.C.; Chen, C.L.; Chiou, S.H.; Huang, H.S. New approaches of PARP-1 inhibitors in human lung cancer cells and cancer stem-like cells by some selected anthraquinone-derived small molecules. PLoS One, 2013, 8(2)e56284
[http://dx.doi.org/10.1371/journal.pone.0056284] [PMID: 23451039]
[30]
Iwashita, A.; Hattori, K.; Yamamoto, H.; Ishida, J.; Kido, Y.; Kamijo, K.; Murano, K.; Miyake, H.; Kinoshita, T.; Warizaya, M.; Ohkubo, M.; Matsuoka, N.; Mutoh, S. Discovery of quinazolinone and quinoxaline derivatives as potent and selective poly(ADP-ribose) polymerase-1/2 inhibitors. FEBS Lett., 2005, 579(6), 1389-1393.
[http://dx.doi.org/10.1016/j.febslet.2005.01.036] [PMID: 15733846]
[31]
Hattori, K.; Kido, Y.; Yamamoto, H.; Ishida, J.; Kamijo, K.; Murano, K.; Ohkubo, M.; Kinoshita, T.; Iwashita, A.; Mihara, K.; Yamazaki, S.; Matsuoka, N.; Teramura, Y.; Miyake, H. Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase. J. Med. Chem., 2004, 47(17), 4151-4154.
[http://dx.doi.org/10.1021/jm0499256] [PMID: 15293985]
[32]
Hattori, K.; Kido, Y.; Yamamoto, H.; Ishida, J.; Iwashita, A.; Mihara, K. Rational design of conformationally restricted quinazolinone inhibitors of poly(ADP-ribose)polymerase. Bioorg. Med. Chem. Lett., 2007, 17(20), 5577-5581.
[http://dx.doi.org/10.1016/j.bmcl.2007.07.091] [PMID: 17804225]
[33]
Orvieto, F.; Branca, D.; Giomini, C.; Jones, P.; Koch, U.; Ontoria, J.M.; Palumbi, M.C.; Rowley, M.; Toniatti, C.; Muraglia, E. Identification of substituted pyrazolo[1,5-a]quinazolin-5(4H)-one as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(15), 4196-4200.
[http://dx.doi.org/10.1016/j.bmcl.2009.05.113] [PMID: 19541484]
[34]
Giannini, G.; Battistuzzi, G.; Vesci, L.; Milazzo, F.M.; De Paolis, F.; Barbarino, M.; Guglielmi, M.B.; Carollo, V.; Gallo, G.; Artali, R.; Dallavalle, S. Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold. Bioorg. Med. Chem. Lett., 2014, 24(2), 462-466.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.048] [PMID: 24388690]
[35]
Kulkarni, S.S.; Singh, S.; Shah, J.R.; Low, W-K.; Talele, T.T. Synthesis and SAR optimization of quinazolin-4(3H)-ones as poly(ADP-ribose)polymerase-1 inhibitors. Eur. J. Med. Chem., 2012, 50, 264-273.
[http://dx.doi.org/10.1016/j.ejmech.2012.02.001] [PMID: 22365563]

Rights & Permissions Print Cite
Article Metrics
20
© 2024 Bentham Science Publishers | Privacy Policy