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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

Synthesis and In Silico Studies of Quinazolinones as PARP-1 Inhibitors

Author(s): Maneesh Guleria, Adarsh Kumar, Ankit Kumar Singh and Pradeep Kumar*

Volume 27, Issue 9, 2024

Published on: 25 September, 2023

Page: [1329 - 1343] Pages: 15

DOI: 10.2174/1386207326666230905153443

Price: $65

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Abstract

Background: Cancer is a leading threat to humankind, accounting for nearly one million deaths in 2018, and the expected number of cancer-related deaths in 2040 is more than 16 million. The most common causes of cancer deaths are lung, colorectal, stomach, liver and breast cancer, while the highest number of new cancer cases belong to lung, breast, colorectal, prostate, stomach and liver cancer.

Introduction: PARP-1 is an enzyme that plays an important role in DNA repair, cell propagation/survival and death due to its influence on numerous biological processes. Quinazolinones represent an important scaffold in medicinal chemistry and have a broad spectrum of biological activities.

Methods: In this study, we have synthesized quinazolinones by reaction of 2-aminobenzamide and substituted aldehydes. Molecular docking studies of synthesized compounds were performed for their PARP-1 binding affinities using Schrodinger 2016 software. In silico ADME studies were also performed for the synthesized compounds using the QikProp tool of Schrodinger software.

Results: Results of molecular docking studies indicated that synthesized quinazolinones had a good affinity towards active site of PARP-1 and compound 4 had the best docking score (-10.343). Results of ADME studies indicated the drug-like properties of synthesized compounds, which make them suitable drug candidates.

Conclusion: All the synthesized compounds have a better docking score than niraparib (-9.05). Further, the synthesized compounds have a favorable ADME profile. Therefore, they may serve as important leads in discovering PARP-1 inhibitors.

Keywords: Cancer, PARP-1, quinazolinones, molecular docking studies, ADME, cancer cases.

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[1]
Kumar, A.; Bhagat, K.K.; Singh, A.K.; Singh, H.; Angre, T.; Verma, A.; Khalilullah, H.; Jaremko, M.; Emwas, A.H.; Kumar, P. Medicinal chemistry perspective of pyrido[2,3- d]pyrimidines as anticancer agents. RSC Advances, 2023, 13(10), 6872-6908.
[http://dx.doi.org/10.1039/D3RA00056G] [PMID: 36865574]
[2]
Kumar, A.; Singh, A.K.; Singh, H.; Vijayan, V.; Kumar, D.; Naik, J.; Thareja, S.; Yadav, J.P.; Pathak, P.; Grishina, M.; Verma, A.; Khalilullah, H.; Jaremko, M.; Emwas, A.H.; Kumar, P. Nitrogen containing heterocycles as anticancer agents: A medicinal chemistry perspective. Pharmaceuticals, 2023, 16(2), 299-368.
[http://dx.doi.org/10.3390/ph16020299] [PMID: 37259442]
[3]
Angre, T; Kumar, A; Singh, AK; Thareja, S; Kumar, P Role of collagen regulators in cancer treatment: A comprehensive review. Anti-Cancer Agents Med. Chem., 2022, 22(17), 2956-2984.
[4]
Jagtap, P.; Szabó, C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat. Rev. Drug Discov., 2005, 4(5), 421-440.
[http://dx.doi.org/10.1038/nrd1718] [PMID: 15864271]
[5]
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]
[6]
Rouleau, M.; Patel, A.; Hendzel, M.J.; Kaufmann, S.H.; Poirier, G.G. PARP inhibition: PARP1 and beyond. Nat. Rev. Cancer, 2010, 10(4), 293-301.
[http://dx.doi.org/10.1038/nrc2812] [PMID: 20200537]
[7]
Langelier, M.F.; Planck, J.L.; Roy, S.; Pascal, J.M. Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1. Science, 2012, 336(6082), 728-732.
[http://dx.doi.org/10.1126/science.1216338] [PMID: 22582261]
[8]
Ali, A.A.E.; Timinszky, G.; Arribas-Bosacoma, R.; Kozlowski, M.; Hassa, P.O.; Hassler, M.; Ladurner, A.G.; Pearl, L.H.; Oliver, A.W. The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks. Nat. Struct. Mol. Biol., 2012, 19(7), 685-692.
[http://dx.doi.org/10.1038/nsmb.2335] [PMID: 22683995]
[9]
Loeffler, P.A.; Cuneo, M.J.; Mueller, G.A.; DeRose, E.F.; Gabel, S.A.; London, R.E. Structural studies of the PARP-1 BRCT domain. BMC Struct. Biol., 2011, 11(1), 37.
[http://dx.doi.org/10.1186/1472-6807-11-37] [PMID: 21967661]
[10]
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]
[11]
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]
[12]
Schiewer, M.J.; Mandigo, A.C.; Gordon, N.; McNair, C.; Lallas, C.D.; Trabulsi, E.J.; Leiby, B.; Knudsen, K.E. PARP-1 regulation of DNA repair factor availability. J. Clin. Oncol., 2019, 37(7_suppl), 269-269.
[http://dx.doi.org/10.1200/JCO.2019.37.7_suppl.269]
[13]
Jiang, X.; Li, W.; Li, X.; Bai, H.; Zhang, Z. Current status and future prospects of PARP inhibitor clinical trials in ovarian cancer. Cancer Manag. Res., 2019, 11, 4371-4390.
[http://dx.doi.org/10.2147/CMAR.S200524] [PMID: 31191001]
[14]
Abu-Hashem, A.A.; Abu-Zied, K.M.; AbdelSalam Zaki, M.E.; El-Shehry, M.F.; Awad, H.M.; Khedr, M.A. Design, synthesis, and anticancer potential of the enzyme (parp-1) inhibitor with computational studies of new triazole, thiazolidinone, - thieno [2, 3-d] pyrimidinones. Lett. Drug Des. Discov., 2020, 17(6), 799-817.
[http://dx.doi.org/10.2174/1570180817666200117114716]
[15]
Verma, S.; Pathania, A.S.; Baranwal, S.; Kumar, P. Synthesis and in silico studies of quinazolinone derivatives as PARP-1 inhibitors. Lett. Drug Des. Discov., 2020, 17(12), 1552-1565.
[http://dx.doi.org/10.2174/1570180817999200719152959]
[16]
Chawla, A.; Batra, C. Recent advances of quinazolinone derivatives as marker for various biological activities. Inter. Res. J. Pharm., 2013, 4(3), 49-58.
[http://dx.doi.org/10.7897/2230-8407.04309]
[17]
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]
[18]
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]
[19]
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]
[20]
Kavitha, K.; Srinivasan, N.; Haribabu, Y. A review on quinazolinone and its derivatives with diverse biological activities. World J. Pharm. Pharm. Sci., 2018, 7(4), 628-649.
[21]
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]
[22]
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.
[23]
Rajput, R.; Mishra, A.P. A review on biological activity of quinazolinones. Int. J. Pharma Sci., 2012, 4(2), 66-70.
[24]
Zhu, S.; Wang, J.; Chandrashekar, G.; Smith, E.; Liu, X.; Zhang, Y. Synthesis and evaluation of 4-quinazolinone compounds as potential antimalarial agents. Eur. J. Med. Chem., 2010, 45(9), 3864-3869.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.040] [PMID: 20538379]
[25]
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.
[26]
Wang, Y.Q.; Wang, P.Y.; Wang, Y.T.; Yang, G.F.; Zhang, A.; Miao, Z.H. An update on poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors: Opportunities and challenges in cancer therapy. J. Med. Chem., 2016, 59(21), 9575-9598.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00055] [PMID: 27416328]
[27]
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]
[28]
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]
[29]
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]
[30]
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]
[31]
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]
[32]
Kim, N.Y.; Cheon, C.H. Synthesis of quinazolinones from anthranilamides and aldehydes via metal-free aerobic oxidation in DMSO. Tetrahedron Lett., 2014, 55(15), 2340-2344.
[http://dx.doi.org/10.1016/j.tetlet.2014.02.065]
[33]
Van Den Driessche, G.; Fourches, D. Adverse drug reactions triggered by the common HLA-B*57:01 variant: A molecular docking study. J. Cheminform., 2017, 9(1), 13.
[http://dx.doi.org/10.1186/s13321-017-0202-6] [PMID: 28303164]
[34]
Madhavi Sastry, G.; 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]
[35]
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]
[36]
Sharma, V.; Sharma, P.C.; Kumar, V. In silico molecular docking analysis of natural pyridoacridines as anticancer agents. Adv. Chem., 2016, 2016(7), 1-9.
[http://dx.doi.org/10.1155/2016/5409387]
[37]
Deep, A.; Singh, J.; Kumar, M.; Mansuri, R.; Sahoo, G.C. 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]
[38]
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]
[39]
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]
[40]
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]
[41]
Graziani, G.; Szabó, C. Clinical perspectives of PARP inhibitors. Pharmacol. Res., 2005, 52(1), 109-118.
[http://dx.doi.org/10.1016/j.phrs.2005.02.013] [PMID: 15911339]
[42]
Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem., 1999, 1(1), 55-68.
[http://dx.doi.org/10.1021/cc9800071] [PMID: 10746014]
[43]
Shahbazi, S.; Sahrawat, T.R.; Ray, M.; Dash, S.; Kar, D.; Singh, S. Drug targets for cardiovascular-safe anti-inflammatory: In silico rational drug studies. PLoS One, 2016, 11(6), e0156156.
[http://dx.doi.org/10.1371/journal.pone.0156156] [PMID: 27258084]
[44]
Vattathara, J.J.; Prakash, O.; Subhramanian, S.; Satheeshkumar, M.K.; Xavier, T.; Anil, M.; Pillai, G.S.; Anandakuttan, A.; Radhakrishnan, S.; Sivanarayanan, T.B.; Akk, U.; Mohan, C.G.; Menon, K.N. Substrate specifc inhibitor designed against the immunomodulator GMF-beta reversed the experimental autoimmune encephalomyelitis. Sci. Rep., 2020, 10(1), 3790.
[http://dx.doi.org/10.1038/s41598-020-60710-2] [PMID: 32123210]

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