Novel 3-Substituted-2, 3-Dihydro-2-Thioxoquinazolin-4-(1H)-one derivative as Anticonvulsants: Synthesis, Molecular Docking and Pharmacological Screening

Author(s): Nimisha jain, Pradeep Kumar Singour*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 6 , 2020


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Abstract:

Background: According to the World Health Organization, 50 million people worldwide are suffering from epilepsy, making it one of the most common neurological diseases globally. 2,3 disubstituted quinazolinone-4-one derivatives endowed with various pharmacological activity, particularly having anticonvulsant action.

Objectives: The aim of this study was to synthesize 3-Substituted-2,3-Dihydro-2-thioxoquinazolin- 4-(1H)-one derivative and evaluate for anticonvulsant activity and neurotoxicity in order to find an efficient, compound with lesser side effects.

Methods: A novel series of 3-[4-(2-amino-5, 6-dihydro-4(substituted phenyl)-4H-1, 3-oxazin /thiazin-6yl) phenyl]-2, 3-dihyro-2-thioxoquinazolin-4(1H)-one derivatives (4a-4p) were synthesized. The structures of the synthesized compounds were assigned on the basis of spectral data (UV, IR, 1HNMR, 13CNMR and MS) and performed anticonvulsant activity against maximal electroshock test and Subcutaneous Pentylenetetrazole model. Neurotoxicity was assessed using a rotarod apparatus test. The molecular docking study was performed to assess their binding affinities towards Gamma-Aminobutyric Acid type A receptor. A quantitative estimate of drug-likeness was also performed, which calculates the molecular properties and screen the molecules based on drug-likeness rules.

Results: Compounds 4b, 4e, 4j and 4m have shown the highest anticonvulsant activity against tonic seizure with decreased mean duration of tonic hind leg extension of 8.31, 7.35, 8.61 and 8.99 s, respectively in maximal electroshock model and increased onset time clonic convulsion duration of 94.45, 96.65, 93.51 and 91.86 s in Subcutaneous Pentylenetetrazole model. Molecular docking study revealed a better binding affinity with Gamma-Aminobutyric Acid type A receptor.

Conclusion: The compound 4b and 4e emerged out as the pilot molecule with a better anticonvulsant activity without any neurotoxicity. The obtained results showed that compounds 4b and 4e could be useful as a template for future design, optimization, and investigation to produce more active analogs.

Keywords: Epilepsy, gamma-aminobutyric acid, world health organization, molecular properties, drug-likeness rules, pharmacological Screening.

[1]
Joshi, R.; Tripathi, M.; Gupta, P.; Gulati, S.; Gupta, Y.K. Adverse effects & drug load of antiepileptic drugs in patients with epilepsy: Monotherapy versus polytherapy. Indian J. Med. Res., 2017, 145(3), 317-326.
[PMID: 28749393]
[2]
Bialer, M. Chemical properties of antiepileptic drugs (AEDs). Adv. Drug Deliv. Rev., 2012, 64(10), 887-895.
[http://dx.doi.org/10.1016/j.addr.2011.11.006] [PMID: 22210279]
[3]
White, H.S. Preclinical development of antiepileptic drugs: past, present, and future directions. Epilepsia, 2003, 44(Suppl. 7), 2-8.
[http://dx.doi.org/10.1046/j.1528-1157.44.s7.10.x] [PMID: 12919332]
[4]
Khan, I.; Zaib, S.; Batool, S.; Abbas, N.; Ashraf, Z.; Iqbal, J.; Saeed, A. Quinazolines and quinazolinones as ubiquitous structural fragments in medicinal chemistry: An update on the development of synthetic methods and pharmacological diversification. Bioorg. Med. Chem., 2016, 24(11), 2361-2381.
[http://dx.doi.org/10.1016/j.bmc.2016.03.031] [PMID: 27112448]
[5]
Chavan, B.B.; Bhalawane, P.P.; Kolsure, A.K.; Chabukswar, A.R. Synthesis and evaluation of some new 4, 6 disubstituted quinazoline derivatives for antimicrobial and antifungal activities. AJBPR, 2014, 4, 43-46.
[6]
Jain, N.; Jaiswal, J.; Pathak, A.; Singour, P.K. Synthesis, Molecular Docking and Evaluation of 3-4-[2-amino-4- (substitutedphenyl)-2H-[1, 3] oxazin/thiazin-6-yl 2-phenyl-3H-quinazolin- 4-one Derivatives for their Anticonvulsant Activity. Cent. Nerv. Syst. Agents Med. Chem., 2018, 18, 63-73.
[http://dx.doi.org/10.2174/1871524917666170104142033] [PMID: 28056730]
[7]
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]
[8]
Birhan, Y.S.; Bekhit, A.A.; Hymete, A. In vivo antimalarial evaluation of some 2,3-disubstituted-4(3H)-quinazolinone derivatives. BMC Res. Notes, 2015, 8, 589.
[http://dx.doi.org/10.1186/s13104-015-1578-x] [PMID: 26486987]
[9]
Alagarsamy, V.; Pathak, U.S. Synthesis and antihypertensive activity of novel 3-benzyl-2-substituted-3H-[1,2,4]triazolo[5,1-b]quinazolin-9-ones. Bioorg. Med. Chem., 2007, 15(10), 3457-3462.
[http://dx.doi.org/10.1016/j.bmc.2007.03.007] [PMID: 17391966]
[10]
Alagarsamy, V.; Solomon, V.R.; Sheorey, R.V.; Jayakumar, R. Synthesis of 3-(3- Ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones as novel class of Analgesic and Antiinflammatory agents. Chem. Biol. Drug Des., 2009, 73, 471-479.
[http://dx.doi.org/10.1111/j.1747-0285.2009.00794.x] [PMID: 19291107]
[11]
Javaid, K.; Saad, S.M.; Rasheed, S.; Moin, S.T.; Syed, N.; Fatima, I.; Salar, U.; Khan, K.M.; Perveen, S.; Choudhary, M.I. 2-Arylquinazolin-4(3H)-ones: A new class of α-glucosidase inhibitors. Bioorg. Med. Chem., 2015, 23(23), 7417-7421.
[http://dx.doi.org/10.1016/j.bmc.2015.10.038] [PMID: 26552899]
[12]
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]
[13]
Decker, M. Novel inhibitors of acetyl- and butyrylcholinesterase derived from the alkaloids dehydroevodiamine and rutaecarpine. Eur. J. Med. Chem., 2005, 40(3), 305-313.
[http://dx.doi.org/10.1016/j.ejmech.2004.12.003] [PMID: 15725500]
[14]
Alagarsamy, V.; Raja Solomon, V.; Parthiban, P.; Dhanabal, K.; Murugesan, S. Saravanan, G.; Anjana, G. Synthesis and pharmacological investigation of novel 4-(4-ethyl phenyl)-1 substituted-4H-[1,2,4] triazolo [4,3-a]-quinazolin-5- ones as new class of H1-antihistaminic agents. J. Heterocycl. Chem., 2008, 45, 709-715.
[http://dx.doi.org/10.1002/jhet.5570450312]
[15]
Avoli, M.; D’Antuono, M.; Louvel, J.; Köhling, R.; Biagini, G.; Pumain, R.; D’Arcangelo, G.; Tancredi, V. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog. Neurobiol., 2002, 68(3), 167-207.
[http://dx.doi.org/10.1016/S0301-0082(02)00077-1] [PMID: 12450487]
[16]
Curia, G.; Lucchi, C.; Vinet, J.; Gualtieri, F.; Marinelli, C.; Torsello, A.; Costantino, L.; Biagini, G. Pathophysiogenesis of mesial temporal lobe epilepsy: is prevention of damage antiepileptogenic? Curr. Med. Chem., 2014, 21(6), 663-688.
[http://dx.doi.org/10.2174/0929867320666131119152201] [PMID: 24251566]
[17]
Nutt, D. GABAA receptors: subtypes, regional distribution, and function. J. Clin. Sleep Med., 2006, 2(2), S7-S11.
[http://dx.doi.org/10.5664/jcsm.26525] [PMID: 17557501]
[18]
Johnston, G.A. GABA(A) receptor channel pharmacology. Curr. Pharm. Des., 2005, 11(15), 1867-1885.
[http://dx.doi.org/10.2174/1381612054021024] [PMID: 15974965]
[19]
Biagini, G.; Panuccio, G.; Avoli, M. Neurosteroids and epilepsy. Curr. Opin. Neurol., 2010, 23(2), 170-176.
[http://dx.doi.org/10.1097/WCO.0b013e32833735cf] [PMID: 20160650]
[20]
Ibrahim, M.K.; El-Adl, K.; Al-Karmalawy, A.A. Design, synthesis, molecular docking and anticonvulsant evaluation of novel 6-iodo- 2-phenyl- 3-substituted-quinazolin-4(3H)-ones. BFOPCU, 2015, 53, 101-116.
[http://dx.doi.org/10.1016/j.bfopcu.2015.05.001]
[21]
Jatav, V.; Mishra, P.; Kashaw, S.; Stables, J.P. CNS depressant and anticonvulsant activities of some novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones. Eur. J. Med. Chem., 2008, 43(9), 1945-1954.
[http://dx.doi.org/10.1016/j.ejmech.2007.12.003] [PMID: 18222569]
[22]
Kumar, P.; Shrivastava, B.; Pandeya, S.N.; Stables, J.P. Design, synthesis and potential 6 Hz psychomotor seizure test activity of some novel 2-(substituted)-3-[substituted]aminoquinazolin-4(3H)-one. Eur. J. Med. Chem., 2011, 46(4), 1006-1018.
[http://dx.doi.org/10.1016/j.ejmech.2011.01.009] [PMID: 21306800]
[23]
Ugale, V.G.; Bari, S.B. Quinazolines: new horizons in anticonvulsant therapy. Eur. J. Med. Chem., 2014, 80(80), 447-501.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.072] [PMID: 24813877]
[24]
Rajasekaran, A.; Rajamanickam, V.; Darlinquine, S. Synthesis of some new thioxoquinazolinone derivatives and a study on their anticonvulsant and antimicrobial activities. Eur. Rev. Med. Pharmacol. Sci., 2013, 17(1), 95-104.
[PMID: 23329529]
[25]
Sallal, Z.A. Synthesis and characterization of new Oxazine, Thiazine and Pyrazol derived from chalcones. Bagh. Sci. Journal., 2014, 11, 477-484.
[http://dx.doi.org/10.21123/bsj.11.2.477-485]
[26]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[27]
Luger, D.; Poli, G.; Wieder, M.; Stadler, M.; Ke, S.; Ernst, M.; Hohaus, A.; Linder, T.; Seidel, T.; Langer, T.; Khom, S.; Hering, S. Identification of the putative binding pocket of valerenic acid on GABAA receptors using docking studies and site-directed mutagenesis. Br. J. Pharmacol., 2015, 172(22), 5403-5413.
[http://dx.doi.org/10.1111/bph.13329] [PMID: 26375408]
[28]
Harrington, E.C. The desirability function. Ind. Qual. Control., 1965, 21, 494-498.
[29]
Bickerton, G.R.; Paolini, G.V.; Besnard, J.; Muresan, S.; Hopkins, A.L. Quantifying the chemical beauty of drugs. Nat. Chem., 2012, 4(2), 90-98.
[http://dx.doi.org/10.1038/nchem.1243] [PMID: 22270643]
[30]
Racine, R.J. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. Clin. Neurophysiol., 1972, 32(3), 281-294.
[http://dx.doi.org/10.1016/0013-4694(72)90177-0] [PMID: 4110397]
[31]
Castel-Branco, M.M.; Alves, G.L.; Figueiredo, I.V.; Falcão, A.C.; Caramona, M.M. The maximal electroshock seizure (MES) model in the preclinical assessment of potential new antiepileptic drugs. Methods Find. Exp. Clin. Pharmacol., 2009, 31(2), 101-106.
[http://dx.doi.org/10.1358/mf.2009.31.2.1338414] [PMID: 19455265]
[32]
Orloff, M.J.; Williams, H.L.; Pfeiffer, C.C. Timed intravenous infusion of metrazol and strychnine for testing anticonvulsant drugs. Proc. Soc. Exp. Biol. Med., 1949, 70(2), 254-257.
[http://dx.doi.org/10.3181/00379727-70-16891] [PMID: 18112778]
[33]
Conagin, A.; Barbin, D.; Demetrio, C.G.B. modified dunnett’s test for a randomized complete block design. Rev. Bras. Biol., 2011, 29, 599-610.
[34]
Dunham, N.W.; Miya, T.S. A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc Am Pharm Assoc, 1957, 46(3), 208-209.
[http://dx.doi.org/10.1002/jps.3030460322] [PMID: 13502156]
[35]
Kupferberg, H.J. Antiepileptic drug development program: a cooperative effort of government and industry. Epilepsia, 1989, 30(Suppl. 1), S51-S56.
[http://dx.doi.org/10.1111/j.1528-1157.1989.tb05815.x] [PMID: 2776711]


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VOLUME: 17
ISSUE: 6
Year: 2020
Page: [757 - 771]
Pages: 15
DOI: 10.2174/1570180816666191024090857
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