Design and Development of Novel 2-(Morpholinyl)-N-substituted Phenylquinazolin-4-amines as Selective COX-II Inhibitor

Author(s): Bhushan R. Dravyakar*, Pramod B. Khedekar, Tabassum Khan, Atul P. Sherje, Kavit N. Patel, Vasanti Suvarna

Journal Name: Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Formerly Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents

Volume 18 , Issue 1 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: A novel series of 2-(Morpholin-4-yl)-N-phenylquinazolin-4- amine derivatives were synthesized and confirmed with spectral and elemental techniques.

Methods: The compounds were tested for analgesic and anti-inflammatory activity by various pain models in rodents whereas the selectivity towards COX-2 receptor is determined by in vitro assay.

Results: Screening results of compounds exhibited comparable biological activity with that of standard compound Indomethacin used for study. Compound 5d was found to be significantly potent with respect to its anti-inflammatory and analgesic activity with substantial COX-II selectivity.

Conclusion: In silico analysis by molecular docking and 3D-QSAR studies justifies activity profile of compound 5d, suggesting that it may have potential for further evaluation and development as lead molecule for therapy in pain management.

Keywords: 3D-QSAR, analgesic, anti-inflammatory, COX II inhibitor, molecular docking, quinazoline.

[1]
Singh, G.; Triadafilopoulos, G. Epidemiology of NSAID induced gastrointestinal complications. J. Rheumatol. Suppl., 1999, 56, 18-24.
[2]
Smith, W.L. Dewitt, D.L. Prostaglandin endoperoxide H synthases-1 and -2. Adv. Immunol., 1996, 62, 167-215.
[3]
Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas, R.; Davis, B.; Hochberg, M.; Kvien, T.; Schnitzer, K. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N. Engl. J. Med., 2000, 343(21), 1520-1524.
[4]
Naesdal, J.; Brown, K. NSAID-associated adverse effects and acid control aids to prevent them: A review of current treatment options. Drug Saf., 2006, 29(2), 119-132.
[5]
Nanda, S.; Ganguli, A.; Chakraborty, R. Antibacterial activity of some 3-(Arylideneamino)-2-phenylquina-zoline-4(3H)-ones: Synthesis and preliminary QSAR Studies. Molecules, 2007, 12(10), 2413-2419.
[6]
Kunes, J.; Bazant, J.; Pour, M.; Waisser, K.; Slosarek, M. Quinazoline derivatives with antitubercular activity. IlFarmaco, 2000, 55, 725-732.
[7]
Saravanan, G.; Alagarsamy, V.; Chinnasamy, R. Synthesis, analgesic, anti-inflammatory and ulcerogenic properties of some novel N′-((1-(substituted amino)methyl)-2-oxoindolin-3-ylidene)- 4-(2-(methyl/ phenyl)-4-oxoquinazolin-3(4H)-yl)benzohydrazide derivatives. Drug Discov. Ther., 2012, 6(2), 78-83.
[8]
Nagar, A.A.; Rathi, L.G.; Chugh, N.; Pise, V.J.; Bendale, A. Microwave assisted one pot synthesis of 2, 3-di-substituted Quinazolin-4-(3h)-ones and their potential biological activity. Der. Pharma Chem., 2010, 2(3), 37-43.
[9]
Michael, J.P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep., 2003, 20(5), 476-493.
[10]
Hansen, H.; Krutz, B.; Sifringer, M.; Stefovska, V.; Bittigau, P.; Pragst, F.; Marsicano, G.; Lutz, B.; Ikonomidou, C. Cannabinoids enhance susceptibility of immature brain to ethanol neurotoxicity. Ann. Neurol., 2008, 64(1), 42-52.
[11]
Frederick, M.; Henry, T. Piperidine, morpholine and piperazine derivatives. GB19680027501, 1968.
[12]
Dravyakar, B.R.; Khedekar, P.B. Study of synthesis of novel N, 2-diphenylquinazolin-4-amine derivatives as an anti-inflammatory and analgesic agent. Pharma Chem., 2012, 4(2), 699-706.
[13]
OECD/OCDE Guidelines for the testing of chemicals. Guideline 423: Repeated dose oral toxicity study in rodents. Adopted 21st September, Paris, 1998.
[14]
Ghante, M.; Bhusari, K.; Durugkar, N.; Jain, N.; Warokar, A. Bronchorelaxant, mast cell stabilizing, anti-inflammatory and antioxidant activity of Randia dumetorum (Retz.) Lamk. extracts. Acta Polanae Pharmaceutica-Drug Res, 2012, 69(3), 465-474.
[15]
Vogel, H.G. Drug discovery and evaluation: Pharma cological assay, 3rd ed; Springer-Verlag Berlin Heidelberg: New York, 2005.
[16]
Turner, R. Screening methods in pharmacology, 1st ed; Elseveir: Amsterdam, 1971.
[17]
Umapathy, E.; Ndebia, E.; Meeme, A.; Menziwa, B.; Nkeh-Chungag, B.; Iputo, J. An experimental evaluation of Albuca setosa aqueous extract on membrane stabilization, protein denaturation and white blood cell migration during acute inflammation. J. Med. Plants Res., 2010, 4(9), 789-795.
[18]
Okoli, C.; Akah, P.; Onuoha, N.; Okoye, T.; Nwoye, A.; Nworu, C. Acanthus montanus: An experimental evaluation of the antimicrobial, anti-inflammatory and immunological properties of a traditional remedy for furuncles. BMC Compl. Alt. Med., 2008, 8, 18-27.
[19]
Vijaya Raj, K.; Narayana, B.; Ashalatha, B.; Sarojani, B. Synthesis of some bioactive 2-bromo-5-methoxy-N′-[4-(aryl)-1,3-thiazol-2-yl]benzohydrazide derivatives. Eur. J. Med. Chem., 2007, 42(3), 425-429.
[20]
Vigorita, M.G.; Ottanà, R.; Monforte, F.; Maccari, R.; Monforte, M.T.; Trovato, A. Chiral 3,3′-(1,2-Ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] with anti-inflammatory activity. Part 11: Evaluation of COX-2 selectivity and modeling. Bioorg. Med. Chem., 2005, 11(6), 999-1006.
[21]
Chikhale, R.; Pant, A.; Menghani, S.; Khedekar, P. Development of dual inhibitors targeting DprE1and AHAS for treatment of Mycobacterium tuberculosis infection. BMC Infect. Dis., 2014, 14(Suppl. 3), E24.
[22]
Ajmani, S.; Jadhav, K.; Kulkarni, A. Three-dimensional QSAR using the k-Nearest neighbor method and its interpretation. J. Chem. Inf. Model., 2006, 46(1), 24-31.


open access plus

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 18
ISSUE: 1
Year: 2019
Published on: 06 February, 2019
Page: [4 - 25]
Pages: 22
DOI: 10.2174/1871523017666181022144053

Article Metrics

PDF: 55
HTML: 4