N-arylmethylideneaminophthalimide: Design, Synthesis and Evaluation as Analgesic and Anti-inflammatory Agents

Author(s): Nasimossadat Banarouei, Asghar Davood*, Hamed Shafaroodi, Ghazaleh Saeedi, Abbas Shafiee

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 8 , 2019

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Graphical Abstract:


Background and Objective: N-aryl derivatives of phthalimide and 4-nitro phthalimide have demonstrated cyclooxygenase inhibitory activity. Also, they possess excellent analgesic and antiinflammatory activity. In this work, a new series of N-arylmethylideneamino derivatives of phthalimide and 4-nitro phthalimide were designed and synthesized.

Methods: The designed compounds were synthesized by condensation of the appropriate aldehyde and N-aminophthalimide in ethanol at room temperature at PH around 3. Their analgesic and antiinflammatory activity were evaluated by acetic acid-induced pain test and carrageenan-induced paw edema test in mice and rats, respectively.

Results and Conclusion: The details of the synthesis and chemical characterization of the analogs are described. In vivo screening showed compounds 3a, 3b, 3f and 3h were the most potent analgesic compounds. In addition, compounds 3a, 3c, 3d, 3e and 3j indicated comparable anti-inflammatory activity to indomethacin as a reference drug.

Keywords: Acetic acid-induced pain, analgesic, anti-inflammatory, carrageenan-induced paw edema, phthalimide, N-arylmethylideneaminophthalimide.

Caraceni, A.; Gorni, G.; Zecca, E.; De Conno, F. More on the use of nonsteroidal anti-inflammatories in the management of cancer pain. J. Pain Symptom Manage., 2001, 21, 89-91.
Ferreira, M.L.; Herbert, R.D.; Ferreira, P.H.; Latimer, J.; Ostelo, R.W.; Grotle, M.; Barrett, B. The smallest worthwhile effect of nonsteroidal anti-inflammatory drugs and physiotherapy for chronic low back pain: A benefit–harm trade-off study. J. Clin. Epidemiol., 2013, 66, 1397-1404.
Gnjidic, D.; Blyth, F.M.; Le Couteur, D.G.; Cumming, R.G.; McLachlan, A.J.; Handelsman, D.J.; Seibel, M.; Waite, L.; Naganathan, V. Nonsteroidal anti-inflammatory drugs (NSAIDs) in older people: Prescribing patterns according to pain prevalence and adherence to clinical guidelines. Pain, 2013, 155, 1814-1820.
Hassa, H.; Oge, T.; Aydin, Y.; Burkankulu, D. Comparison of nonsteroidal anti-inflammatory drugs and misoprostol for pain relief during and after hysterosalpingography: Prospective, randomized, controlled trial. J. Minim. Invasive Gynecol., 2014, 21, 762-766.
Cudaback, E.; Jorstad, N.L.; Yang, Y.; Montine, T.J.; Keene, C.D. Therapeutic implications of the prostaglandin pathway in Alzheimer’s disease. Biochem. Pharmacol., 2014, 88, 565-572.
Xiong, S.L.; Liu, X.; Yi, G.H. High-density lipoprotein induces cyclooxygenase-2 expression and prostaglandin I-2 release in endothelial cells through sphingosine kinase-2. Mol. Cell. Biochem., 2014, 389, 197-207.
de Moraes, C.N.; Maia, L.; de Lima, P.F.; Dias, M.C.; Raposo-Ferreira, T.M.M.; Sudano, M.J.; Junior, J.B.; Oba, E. Temporal analysis of prostaglandin F2α receptor, caspase 3, and cyclooxygenase 2 messenger RNA expression and prostaglandin F2α receptor and cyclooxygenase 2 protein expression in endometrial tissue from multiparous Nelore (Bos taurus indicus) cows treated with cloprostenol sodium during puerperium. Theriogenology, 2015, 83, 276-284.
Grim, T.W.; Ghosh, S.; Hsu, K-L.; Cravatt, B.F.; Kinsey, S.G.; Lichtman, A.H. Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models. Pharmacol. Biochem. Behav., 2014, 124, 405-411.
Alanazi, A.M.; El-Azab, A.S.; Al-Suwaidan, I.A.; ElTahir, K.E.H.; Asiri, Y.A.; Abdel-Aziz, N.I.; Abdel-Aziz, A.A.M. Structure-based design of phthalimide derivatives as potential cyclooxygenase-2 (COX-2) inhibitors: Anti-inflammatory and analgesic activities. Eur. J. Med. Chem., 2015, 92, 115-123.
Arellano, F.M.; Yood, M.U.; Wentworth, C.E.; Oliveria, S.A.; Rivero, E.; Verma, A.; Rothman, K.J. Use of cyclo-oxygenase 2 inhibitors (COX-2) and prescription non-steroidal anti-inflammatory drugs (NSAIDS) in UK and USA populations. Implications for COX-2 cardiovascular profile. Pharmacoepidemiol. Drug Saf., 2006, 15, 861-872.
Boursinos, L.A.; Karachalios, T.; Poultsides, L.; Malizos, K.N. Do steroids, conventional non-steroidal anti-inflammatory drugs and selective Cox-2 inhibitors adversely affect fracture healing? J. Musculoskelet. Neuronal Interact., 2009, 9, 44-52.
Tanaka, K.I.; Suemasu, S.; Ishihara, T.; Tasaka, Y.; Arai, Y.; Mizushima, T. Inhibition of both COX-1 and COX-2 and resulting decrease in the level of prostaglandins E2 is responsible for non-steroidal anti-inflammatory drug (NSAID)-dependent exacerbation of colitis. Eur. J. Pharmacol., 2009, 603, 120-132.
Grover, J.; Kumar, V.; Singh, V.; Bairwa, K.; Sobhia, M.E.; Jachak, S.M. Synthesis, biological evaluation, molecular docking and theoretical evaluation of ADMET properties of nepodin and chrysophanol derivatives as potential cyclooxygenase (COX-1, COX-2) inhibitors. Eur. J. Med. Chem., 2014, 80, 47-56.
Kim, K.J.; Choi, M.J.; Shin, J.S.; Kim, M.; Choi, H.E.; Kang, S.M.; Jin, J.H.; Lee, K.T.; Lee, J.Y. Synthesis, biological evaluation, and docking analysis of a novel family of 1-methyl-1H-pyrrole-2,5-diones as highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. Bioorg. Med. Chem. Lett., 2014, 24, 1958-1962.
Yusup, G.; Akutsu, Y.; Mutallip, M.; Qin, W.; Hu, X.; Komatsu-Akimoto, A.; Hoshino, I.; Hanari, N.; Mori, M.; Akanuma, N.; Isozaki, Y.; Matsubara, H.A. COX-2 inhibitor enhances the antitumor effects of chemotherapy and radiotherapy for esophageal squamous cell carcinoma. Int. J. Oncol., 2014, 44, 1146-1152.
Davood, A.; Alipour, E.; Shafiee, A. Efficient synthesis of imidazole derivatives: An important synthon for the preparation of biologically active compounds. Turk. J. Chem., 2008, 32, 389-395.
Iman, M.; Davood, A.; Nematollahi, A.R.; Dehpoor, A.R.; Shafiee, A. Design and synthesis of new 1,4-dihydropyridines containing 4(5)-chloro-5(4)-imidazolyl substituent as a novel calcium channel blocker. Arch. Pharm. Res., 2011, 34, 1417-1426.
Sarkandi, D.N.; Firoozpour, L.; Asadipour, A.; Sheibani, V.; Asli, M.A.M.; Davood, A.; Shafiee, A.; Foroumadi, A. Synthesis of 1-Benzyl-4-[2-(5-phenyl-1,3,4-thiadiazole-2-yl)aminoethyl] piperidine as potential alzheimer’s disease modifying agent. Asian J. Chem., 2011, 23, 2503-2505.
Alanazi, A.M.; El-Azab, A.S.; Al-Suwaidan, I.A.; Eltahir, K.E.H.; Asiri, Y.A.; Abdel-Aziz, N.I.; Abdel-Aziz, A.A.M. Structure-based design of phthalimide derivatives as potential cyclooxygenase-2 (COX-2) inhibitors: Anti-inflammatory and analgesic activities. Eur. J. Med. Chem., 2015, 92, 115-123.
Avila, C.M.; Romeiro, N.C.; Sperandio da Silva, G.M.; Sant’Anna, C.M.R.; Barreiro, E.J.; Fraga, C.A.M. Development of new CoMFA and CoMSIA 3D-QSAR models for anti-inflammatory phthalimide-containing TNFα modulators. Bioorg. Med. Chem., 2006, 14, 6874-6885.
Zav’yalov, S.I.; Zavozin, A.G.; Kulikova, L.B.; Ezhova, G.I.; Kravchenko, N.E. Synthesis of N-aryl derivatives of succinimide and phthalimide. Pharm. Chem. J., 1997, 31, 43-44.
Lima, L.M.; Castro, P.; Machado, A.L.; Fraga, C.A.M.; Lugnier, C.; de Moraes, V.L.G.; Barreiro, E.J. Synthesis and anti-inflammatory activity of phthalimide derivatives, designed as new thalidomide analogues. Bioorg. Med. Chem., 2002, 10, 3067-3073.
Meyer-Kirchrath, J.; Schrör, K. Cyclooxygenase-2 inhibition and side-effects of non-steroidal anti-inflammatory drugs in the gastrointestinal tract. Curr. Med. Chem., 2000, 7, 1121-1129.
Lazzaroni, M.; Bianchi Porro, G. Gastrointestinal side-effects of traditional non-steroidal anti-inflammatory drugs and new formulations. Aliment. Pharmacol. Ther., 2004, 20, 48-58.
Maund, E.; McDaid, C.; Rice, S.; Wright, K.; Jenkins, B.; Woolacott, N. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: A systematic review. Br. J. Anaesth., 2001, 106, 292-297.
Iman, M.; Shafaroodi, H.; Davood, A.; Abedini, M.; Pishva, P.; Taherkhani, M.; Dehpour, A.R.; Shafiee, A. Design and synthesis of 2-(arylmethylideneamino) isoindolines as new potential analgesic and anti-inflammatory agents: A molecular hybridization approach. Curr. Pharm. Des., 2016, 22, 5760-5766.
Onwukaeme, N.D. Anti-inflammatory activities of flavonoids of Baphia nitida Lodd. (Leguminosae) on mice and rats. J. Ethnopharmacol., 1995, 46, 121-124.
Büyükokuroğlu, M.E. Anti-inflammatory and antinociceptive properties of dantrolene sodium in rats and mice. Pharmacol. Res., 2002, 45, 455-460.
Badilla, B.; Arias, A.Y.; Arias, M.; Mora, G.A.; Poveda, L.J. Anti-inflammatory and antinociceptive activities of Loasa speciosa in rats and mice. Fitoterapia, 2003, 74, 45-51.
Mujumdar, A.M.; Misar, A.V. Anti-inflammatory activity of Jatropha curcas roots in mice and rats. J. Ethnopharmacol., 2004, 90, 11-15.
Kale, M.; Misar, A.V.; Dave, V.; Joshi, M.; Mujumdar, A.M. Anti-inflammatory activity of Dalbergia lanceolaria bark ethanol extract in mice and rats. J. Ethnopharmacol., 2007, 112, 300-304.
Rezaei-S, M.; Dashti-R, M.H.; Emami, T. Anti-nociceptive effect of propranolol on neuropathic and inflammatory pain in rats. Neurosci. Res., 2009, 65(Suppl. 1), S258.

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Article Details

Year: 2019
Published on: 23 April, 2018
Page: [679 - 687]
Pages: 9
DOI: 10.2174/1389557518666180424101009
Price: $65

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