Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Synthesized 2-Trifluoromethylquinazolines and Quinazolinones Protect BV2 and N2a Cells against LPS- and H2O2-induced Cytotoxicity

Author(s): Neeranjini Nallathamby, Chia-Wei Phan, Matej Sova, Luciano Saso and Vikineswary Sabaratnam*

Volume 17, Issue 6, 2021

Published on: 18 December, 2019

Page: [623 - 629] Pages: 7

DOI: 10.2174/1573406416666191218095635

Price: $65

Abstract

Background: Microglia are associated with neuroinflammation, which play a key role in the pathogenesis of neurodegenerative diseases. It has been reported that some quinazolines and quinazolinones possess anti-inflammatory properties. However, the pharmacological properties of certain quinazoline derivatives are still unknown.

Objective: The antioxidant, cytotoxic, and protective effects of a series of synthesized 2- trifluoromethylquinazolines (2, 4, and 5) and quinazolinones (6-8) in lipopolysaccharide (LPS)- murine microglia (BV2) and hydrogen peroxide (H2O2)-mouse neuroblastoma-2a (N2a) cells were investigated.

Method: The antioxidant activity of synthesized compounds was evaluated with ABTS and DPPH assays. The cytotoxic activities were determined by MTS assay in BV2 and N2a cells. The production of nitric oxide (NO) in LPS-induced BV2 microglia cells was quantified.

Results: The highest ABTS and DPPH scavenging activities were observed for compound 8 with 87.7% of ABTS scavenge percentage and 54.2% DPPH inhibition. All compounds were noncytotoxic in BV2 and N2a cells at 5 and 50 μg/mL. The compounds which showed the highest protective effects in LPS-induced BV2 and H2O2-induced N2a cells were 5 and 7. All tested compounds, except 4, also reduced NO production at concentrations of 50 μg/mL. The quinazolinone series 6-8 exhibited the highest percentage of NO reduction, ranging from 38 to 60%. Compounds 5 and 8 possess balanced antioxidant and protective properties against LPS- and H2O2-induced cell death, thus showing great potential to be developed into anti-inflammatory and neuroprotective agents.

Conclusion: Compounds 5 and 7 were able to protect the BV2 and N2a cells against LPS and H2O2 toxicity, respectively, at a low concentration (5 μg/mL). Compounds 6-8 showed potent reduction of NO production in BV2 cells.

Keywords: Antioxidant, anti-inflammatory, neuroprotection, quinazolines, quinazolinones, BV2, N2a.

Graphical Abstract
[1]
Regen, F.; Hellmann-Regen, J.; Costantini, E.; Reale, M. Neuroinflammation and Alzheimer’s disease: implications for microglial activation. Curr. Alzheimer Res., 2017, 14(11), 1140-1148.
[http://dx.doi.org/10.2174/1567205014666170203141717] [PMID: 28164764]
[2]
Gupta, T.; Rohilla, A.; Pathak, A.; Akhtar, M.J.; Haider, M.R.; Shahar Yar, M. Current perspectives on quinazolines with potent biological activities: A review. Synth. Commun., 2017, 48(10), 1099-1127.
[http://dx.doi.org/10.1080/00397911.2018.1431282]
[3]
Hameed, A.; Al-Rashida, M.; Uroos, M.; Ali, S.A. Arshia; Ishtiaq, M.; Khan, K.M. Quinazoline and quinazolinone as important medicinal scaffolds: a comparative patent review (2011-2016). Expert Opin. Ther. Pat., 2018, 28(4), 281-297.
[http://dx.doi.org/10.1080/13543776.2018.1432596] [PMID: 29368977]
[4]
Dolšak, A.; Švajger, U.; Lešnik, S.; Konc, J.; Gobec, S.; Sova, M. Selective Toll-like receptor 7 agonists with novel chromeno[3,4-d]imidazol-4(1H)-one and 2-(trifluoromethyl)quinoline/quinazoline-4-amine scaffolds. Eur. J. Med. Chem., 2019, 179, 109-122.
[http://dx.doi.org/10.1016/j.ejmech.2019.06.030]
[5]
Chatterjee, N.; Das, S.; Bose, D.; Banerjee, S.; Das, S.; Chattopadhyay, D.; Saha, K.D. Exploring the anti-inflammatory activity of a novel 2-phenylquinazoline analog with protection against inflammatory injury. Toxicol. Appl. Pharmacol., 2012, 264(2), 182-191.
[http://dx.doi.org/10.1016/j.taap.2012.07.032] [PMID: 22902631]
[6]
Chayah, M.; Arias, F.; Gallo, M.A. Quinazolinones, quinazolinthiones, and quinazolinimines as nitric oxide synthase inhibitors: synthetic study and biological evaluation. Arch Pharm, 2018, 10-11.
[7]
El-Azab, A.S.; Eltahir, K.E. Design and synthesis of novel 7-aminoquinazoline derivatives: antitumor and anticonvulsant activities. Bioorg. Med. Chem. Lett., 2012, 22(5), 1879-1885.
[http://dx.doi.org/10.1016/j.bmcl.2012.01.071] [PMID: 22326394]
[8]
Beck, H.P.; Kohn, T.; Rubenstein, S.; Hedberg, C.; Schwandner, R.; Hasslinger, K.; Dai, K.; Li, C.; Liang, L.; Wesche, H.; Frank, B.; An, S.; Wickramasinghe, D.; Jaen, J.; Medina, J.; Hungate, R.; Shen, W. Discovery of potent LPA2 (EDG4) antagonists as potential anticancer agents. Bioorg. Med. Chem. Lett., 2008, 18(3), 1037-1041.
[http://dx.doi.org/10.1016/j.bmcl.2007.12.024] [PMID: 18178086]
[9]
Hrast, M.; Rožman, K.; Jukič, M.; Patin, D.; Gobec, S.; Sova, M. Synthesis and structure-activity relationship study of novel quinazolinone-based inhibitors of MurA. Bioorg. Med. Chem. Lett., 2017, 27(15), 3529-3533.
[http://dx.doi.org/10.1016/j.bmcl.2017.05.064] [PMID: 28579123]
[10]
Greiner, J.; Pastor, R.; Cambon, A. Synthesis and spectral characteristics of 2-(perfluoroalkyl)-3,4-dihydro-4-oxoquinazo-lines. J. Fluor. Chem., 1981, 18(2), 185-195.
[http://dx.doi.org/10.1016/S0022-1139(00)82315-5]
[11]
Nallathamby, N.; Serm, L.G.; Raman, J.; Malek, S.N.A.; Vidyadaran, S.; Naidu, M.; Kuppusamy, U.R.; Sabaratnama, V. Identification and in vitro evaluation of lipids from sclerotia of Lignosus rhinocerotis for antioxidant and anti-neuroinflammatory activities. Nat. Prod. Commun., 2016, 11(10), 1485-1490.
[http://dx.doi.org/10.1177/1934578X1601101016] [PMID: 30549604]
[12]
Gangwar, M.; Gautam, M.K.; Sharma, A.K.; Tripathi, Y.B.; Goel, R.K.; Nath, G. Antioxidant capacity and radical scavenging effect of polyphenol rich Mallotus philippenensis fruit extract on human erythrocytes: an in vitro study. ScientificWorldJournal, 2014, 2014279451
[http://dx.doi.org/10.1155/2014/279451] [PMID: 25525615]
[13]
Tan, S.W.; Ramasamy, R.; Abdullah, M.; Vidyadaran, S. Inhibitory effects of palm α-, γ- and δ-tocotrienol on lipopolysaccharide-induced nitric oxide production in BV2 microglia. Cell. Immunol., 2011, 271(2), 205-209.
[http://dx.doi.org/10.1016/j.cellimm.2011.07.012] [PMID: 21839427]
[14]
Ozcelik, O.; Algul, S. Nitric oxide levels in response to the patients with different stage of diabetes. Cell. Mol. Biol., 2017, 63(1), 49-52.
[http://dx.doi.org/10.14715/cmb/2017.63.1.10] [PMID: 28234625]
[15]
Zhang, S.; Yang, L.; Kouadir, M.; Tan, R.; Lu, Y.; Chang, J.; Xu, B.; Yin, X.; Zhou, X.; Zhao, D. PP2 and piceatannol inhibit PrP106-126-induced iNOS activation mediated by CD36 in BV2 microglia. Acta Biochim. Biophys. Sin. (Shanghai), 2013, 45(9), 763-772.
[http://dx.doi.org/10.1093/abbs/gmt074] [PMID: 23838580]
[16]
Bhattacharya, S. Reactive oxygen species and cellular defense system.Free radicals in human health and disease; Springer: New Delhi, 2015, pp. 17-29.
[http://dx.doi.org/10.1007/978-81-322-2035-0_2]
[17]
Santagati, N.A.; Bousquet, E.; Spadaro, A.; Ronsisvalle, G. 4-quinazolinones: synthesis and reduction of prostaglandin E2 production. Farmaco, 1999, 54(11-12), 780-784.
[http://dx.doi.org/10.1016/S0014-827X(99)00102-0] [PMID: 10668179]
[18]
Nakanishi, M.; Rosenberg, D.W. Multifaceted roles of PGE2 in inflammation and cancer. Semin. Immunopathol., 2013, 35(2), 123-137.
[http://dx.doi.org/10.1007/s00281-012-0342-8] [PMID: 22996682]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy