Generic placeholder image

Letters in Drug Design & Discovery

Author(s): Nimisha Jain and Pradeep Kumar Singour*

DOI: 10.2174/1570180816666190222155404

DownloadDownload PDF Flyer Cite As
Novel 3-{4-[2-Amino-4-(Substitutedphenyl)-2H-[1, 3] Oxazin/Thiazin-6-Yl} -2-Phenyl-3H-Quinazolin-4-One Derivatives as Enhancer of GABA Mediated Inhibition: Synthesis, Molecular Modeling and Pharmacological Studies

Page: [199 - 213] Pages: 15

  • * (Excluding Mailing and Handling)

Abstract

Background: According to WHO, the 50 million people worldwide are suffering from epilepsy, making it one of the most common neurological diseases globally. Epilepsy is often characterized by neurobiological, cognitive, psychological and behavioral changes and that may enhance the susceptibility to seizures and affect the quality of life.

Objectives: The aim of the present work was to develop 2, 3 disubstituted 4-(3H)-quinazolinone derivatives in order to find an effective and highly lipophilic compound with lesser side effects and to evaluate them for anticonvulsant and neurotoxic activity.

Methods: A novel series of 3-{4-[2-amino-4-(substitutedphenyl)-2H-[1.3] oxazin/thiazin-6-yl} 2- phenyl-3H-quinazolin-4-one derivatives were synthesized and evaluated for their anticonvulsant activity. The structures of the compound have been confirmed by spectral analysis. The molecular docking study was performed for finding the binding affinity with GABAA receptor in order to rationalize their anticonvulsant activities in a qualitative way. Quantitative estimate of drug-likeness was also performed which calculate the molecular properties and screen the molecules based on drug-likeness rules. Anticonvulsant activities of synthesized compounds were done by using (Maximal electroshock) MES induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in Wistar rats of either sex. None of the compounds demonstrated any sign of neurotoxicity.

Results: Compounds 3-{4-[2-amino-4-(fluorophenyl)-2H- [1, 3] oxazin-6-yl} 2-phenyl-3H quinazolin-4-one (5i) and 3-{4-[2-amino-4-(fluorophenyl)-2H- [1, 3] thiazin -6-yl} 2-phenyl-3H quinazolin-4-one (5n) have shown significant activity against tonic seizure by the MES model and clonic seizure by scPTZ induced seizure model.

Conclusion: These ten novels synthesized compounds had significant anticonvulsant activity. As a result, the compound (5i) and (5n) emerged out as the pilot molecule with a better anticonvulsant activity without any neurotoxicity, while the other compounds have moderate activity. QED analysis of compounds (5i) and (5n) also indicated that these compounds will have good oral absorption. The proposed work is to make efforts towards the development and identification of novel molecules as anticonvulsant agents by the synthesis of some novel quinazolinone derivatives with improved biological activity.

Keywords: Anticonvulsant, molecular docking, GABA, MES, quinazolin-4(3H)-ones, scPTZ, seizures.

Graphical Abstract

[1]
Stafstrom, C.E.; Lionel, C. Seizures and Epilepsy: An Overview for Neuroscientists. Cold Spring Harb. Perspect. Med., 2015, 5, 1-18.
[2]
Falco-Waltera, J.J. Schefferb, I.E.; Fishera R.S. The new definition and classification of seizures and epilepsy. Epilepsy Res., 2018, 139, 73-79.
[3]
Johnston, G.A.R. GABAA Receptor Channel Pharmacology. Curr. Pharm. Des., 2005, 11, 1867-1885.
[4]
Rogawski, M.A.; Loscher, W. The neurobiology of antiepileptic drugs. Nat. Rev. Neurosci., 2004, 5, 553-564.
[5]
Pollard, J.R.; French, J. Antiepileptic drugs in development. Lancet Neurol., 2006, 5, 1064-1067.
[6]
Kalueff, A.; Nutt, D.J. Role of gaba in memory and anxiety. Depress. Anxiety, 1996/1997, 4, 100-110.
[7]
El Far, O.; Betz, H. G-protein-coupled receptors for neurotransmitter amino acids: C-terminal tails, crowded signalosomes. Biochem. J., 2002, 365, 329-336.
[8]
Wang, D.D.; Kriegstein, A.R. Defining the role of GABA in cortical development. J. Physiol., 2009, 587, 1873-1879.
[9]
Nutt, D. GABAA Receptors: Subtypes, Regional Distribution, and Function. J. Clin. Sleep Med., 2006, 2, S7-S11.
[10]
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. B-FOPCU, 2015, 53, 101-116.
[11]
El-Hiti, G.A. Synthesis of substituted quinazolin-4(3H)-ones and quinazolines via directed lithiation. Heterocycles, 2000, 53, 1839-1868.
[12]
El-Hiti, G.A.; Abdel-Megeed, M.F. Synthesis of glycosides containing quinazolin-4(3H)-one ring system. Heterocycles, 2005, 65, 3007-3041.
[13]
Alafeefy, A.M. Kadi, A.A.; A.Al-Deeb, O.; El-Tahir, K.E.H.; A.Al-jaber, N. Synthesis, analgesic and anti-inflammatory evaluation of some novel quinazoline derivatives. Eur. J. Med. Chem., 2010, 45, 4947-4952.
[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.
[15]
Ugale, V.G.; Bari, S.B. Quinazolines: New horizons in anticonvulsant therapy. Eur. J. Med. Chem., 2014, 80, 447-501.
[16]
Zayed, M.F.; Ahmed, H.E.A.; Ihmaid, S.; Omar, A-S.M.; Abdelrahim, A.S. Synthesis and screening of some new fluorinated quinazolinone-sulphonamide hybrids as anticancer agents. J. Taibah Uni. Med. Sci., 2015, 10, 333-339.
[17]
Rosenberg, J.; Gustafsson, F.; Galatius, S.; Hildebrandt, P.R. Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature. Cardiovasc. Drugs Ther., 2005, 19, 301-306.
[18]
Jafari, E.; Khajouei, M.R.; Hassanzadeh, F.; Hakimelahi, G.H.; Khodarahmi, A.K. Quinazolinone and quinazoline derivatives: recent structures with potent antimicrobial and cytotoxic activities. Res. Pharm. Sci., 2016, 11, 1-14.
[19]
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, 7417-7421.
[20]
Jain, N.; Jaiswal, J.; Pathak, A. Singour, P.K. Synthesis, Molecular Docking and Evaluation of3-4-[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.
[21]
Wolfe, J.F.; Rathman, T.L.; Sleevi, M.C.; Campbell, J.A.; Greenwood, T.D. Synthesis and anticonvulsant activity of some new 2-substituted 3-aryl-4(3H)-quinazolinones. J. Med. Chem., 1990, 33, 161-166.
[22]
Ugale, V.G.; Patel, H.M.; Wadodkar, S.G.; Bari, S.B.; Shirkhedkar, A.A.; Surana, S.J. Quinazolino-benzothiazoles: fused pharmacophores as anticonvulsant agents. Eur. J. Med. Chem., 2012, 53, 107-113.
[23]
Alavijeh, M.S.; Chishty, M.; Qaiser, M.Z.; Palmer, A.M. Drug Metabolism and Pharmacokinetics, the Blood-Brain Barrier, and Central Nervous System Drug Discovery. NeuroRx, 2005, 2, 554-571.
[24]
Saravanan, G.; Alagarsamy, V.; Prakash, C.R. Design, synthesis and anticonvulsant activities of novel 1-(substituted/unsubstituted benzylidene)-4-(4-(6,8-dibromo-2-(methyl/phenyl)-4-oxoquinazolin- 3(4H)-yl)phenyl) semicarbazide derivatives. Bioorg. Med. Chem. Lett., 2012, 22, 3072-3078.
[25]
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, 1006-1018.
[26]
Asker, F.W.; Nsaif, L.H. Synthesis and antimicrobial activity of novel of 2, 3-disubstituted quinazolin 4(3H) - one derivatives. Chem. Mat. Res., 2014, 6, 10-16.
[27]
Castel-Branco, M.M.; Alves, G.L.; Figueiredo, I.V.; Falcao, 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, 101-106.
[28]
Racine, R.J. Modification of seizure activity by electrical stimulation: II. Motor seizure. Electroenceph. Clin. Neurophysiol., 1972, 32, 281-294.
[29]
Orlof, 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, 254-257.
[30]
Dunham, N.W.; Miya, T.S. A note on a simple apparatus for detecting neurological deficit in rats and mice. J. Am. Pharm. Assoc., 1957, 46, 208-209.
[31]
Conagin, A.; Barbin, D.; Demétrio, C.G.B. Modified dunnett’s test for a randomized complete block design. Rev. Bras. Biom., 2011, 29, 599-610.
[32]
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, 455-461.
[33]
Luger, D.; Poli, G.; Wieder, M.; Stadler, M.; Kel, 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, 5403-5413.
[34]
Harrington, E.C. The desirability function. Ind Qual Control., 1965, 21, 494-498.
[35]
Bickerton, G.R.; Paolini, G.V.; Besnard, J.; Muresan, S.; Hopkins, A.L. Quantifying the chemical beauty of drugs. Nat. Chem., 2012, 4, 90-98.
[36]
Kupferberg, H.J. Antiepileptic drug development program: a cooperative effort of government and industry. Epilepsia, 1989, 30, S51-S56.