Current Computer-Aided Drug DesignCurrent Computer-Aided Drug DesignCurrent Computer-Aided Drug Design1573-40991875-6697Bentham Science64426410.2174/1573409919666230517121726ChemistryResearch ArticleHybrid Analogues of Hydrazone and Phthalimide: Design, Synthesis, In vivo, In vitro, and In silico Evaluation as Analgesic AgentsShokriShahlainfo@benthamscience.netAyaziHodainfo@benthamscience.netTamjidMohseninfo@benthamscience.netGhoreishiFatemehinfo@benthamscience.netShokriMahsainfo@benthamscience.netBadakhshannouriSogolinfo@benthamscience.netNaderiNimainfo@benthamscience.netDaraeiBahraminfo@benthamscience.netMousaviZahrainfo@benthamscience.netDavoodAsgharinfo@benthamscience.netDepartment of Medicinal Chemistry, Faculty of Pharmaceutical Sciences,, Tehran Islamic Azad Medical Sciences University,Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tehran Islamic Azad Medical Sciences University,Department of Toxicology, School of Pharmacy, Shahid Beheshti University of Medical SciencesDepartment of Toxicology, School of Pharmacy,, Shahid Beheshti University of Medical SciencesDepartment of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences,, Tehran Islamic Azad Medical Sciences University,Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences,, Tehran Islamic Azad Medical Sciences UniversityDepartment of Toxicology, School of Pharmacy,, Shahid Beheshti University of Medical Sciences,Department of Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences,Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences, Tehran Islamic Azad Medical Sciences University,0105202420568569607012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjeid.com/1573-4099/article/view/644264

Background:Based on the anti-inflammatory and analgesic activity of hydrazone and phthalimide, a new series of hybrid hydrazone and phthalimide pharmacophores was prepared and evaluated as analgesic agents.

Methods:The designed ligands were synthesized by reaction of the appropriate aldehydes and 2- aminophthalimide. Analgesic, cyclooxygenase inhibitory, and cytostatic activity of prepared compounds were measured.

Results:All the tested ligands demonstrated significant analgesic activity. Moreover, compounds 3i and 3h were the most potent ligands in the formalin and writhing tests, respectively. Compounds 3g, 3j, and 3l were the most COX-2 selective ligands and ligand 3e was the most potent COX inhibitor with a 0.79 of COX-2 selectivity ratio. The presence of electron-withdrawing moieties with hydrogen bonding ability at the meta position was found to affect the selectivity efficiently, in which compounds 3g, 3l, and 3k showed high COX-2 selectivity, and compound 3k was the most potent one. The cytostatic activity of selected ligands demonstrated that compounds 3e, 3f, 3h, 3k, and 3m showed good analgesic and COX inhibitory activity and were less toxic than the reference drug.

Conclusion:High therapeutic index of these ligands is one of the valuable advantages of these compounds.

2-arylmethylideneaminoisoindoleanalgesiccyclooxygenaseformalinwrithingMTT.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(2), 89-91. doi: 10.1016/S0885-3924(00)00255-4 PMID: 11302119Ferreira, 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(12), 1397-1404. doi: 10.1016/j.jclinepi.2013.02.018 PMID: 24021611Gnjidic, 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, 2014, 155(9), 1814-1820. doi: 10.1016/j.pain.2014.06.009 PMID: 24954164Hassa, 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(5), 762-766. doi: 10.1016/j.jmig.2014.02.014 PMID: 24607797Grim, 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. doi: 10.1016/j.pbb.2014.07.008 PMID: 25058512Alanazi, 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. doi: 10.1016/j.ejmech.2014.12.039 PMID: 25549551Arellano, 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(12), 861-872. doi: 10.1002/pds.1343 PMID: 17086563Boursinos, 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(1), 44-52. PMID: 19240368Tanaka, 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(1-3), 120-132. doi: 10.1016/j.ejphar.2008.11.058 PMID: 19101538Meyer-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(11), 1121-1129. doi: 10.2174/0929867003374219 PMID: 11032962Lazzaroni, M.; Bianchi Porro, G. Gastrointestinal side-effects of traditional non-steroidal anti-inflammatory drugs and new formulations. Aliment. Pharmacol. Ther., 2004, 20(Suppl. 2), 48-58. doi: 10.1111/j.1365-2036.2004.02037.x PMID: 15335413Maund, 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., 2011, 106(3), 292-297. doi: 10.1093/bja/aeq406 PMID: 21285082Grover, 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. doi: 10.1016/j.ejmech.2014.04.033 PMID: 24763362Kim, 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(8), 1958-1962. doi: 10.1016/j.bmcl.2014.02.074 PMID: 24656662Yusup, 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(4), 1146-1152. doi: 10.3892/ijo.2014.2300 PMID: 24535229Davood, 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(9), 1417-1426. doi: 10.1007/s12272-011-0902-9 PMID: 21975802Sarkandi, 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.Claudio Viegas-Junior; Danuello, A.; da Silva Bolzani, V.; Barreiro, E.J.; Fraga, C.A.M. Molecular hybridization: a useful tool in the design of new drug prototypes. Curr. Med. Chem., 2007, 14(17), 1829-1852. doi: 10.2174/092986707781058805 PMID: 17627520Rollas, S.; Küçükgüzel, S. Biological activities of hydrazone derivatives. Molecules, 2007, 12(8), 1910-1939. doi: 10.3390/12081910 PMID: 17960096Lima, P.C.; Lima, L.M.; da Silva, K.C.M.; Léda, P.H.O.; de Miranda, A.L.P.; Fraga, C.A.M.; Barreiro, E.J. Synthesis and analgesic activity of novel N-acylhydrazones and isosters, derived from natural safrole. Eur. J. Med. Chem., 2000, 35(2), 187-203. doi: 10.1016/S0223-5234(00)00120-3 PMID: 10758281Salgın-Gökşen, U.; Gökhan-Kelekçi, N.; Göktaş, Ö.; Köysal, Y.; Kılıç, E.; Işık, Ş.; Aktay, G.; Özalp, M. 1-Acylthiosemicarbazides, 1,2,4-triazole-5(4H)-thiones, 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones: Synthesis, analgesic-anti-inflammatory and antimicrobial activities. Bioorg. Med. Chem., 2007, 15(17), 5738-5751. doi: 10.1016/j.bmc.2007.06.006 PMID: 17587585Zhu, X.; Giordano, T.; Yu, Q.; Holloway, H.W.; Perry, T.A.; Lahiri, D.K.; Brossi, A.; Greig, N.H. Thiothalidomides: novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity. J. Med. Chem., 2003, 46(24), 5222-5229. doi: 10.1021/jm030152f PMID: 14613324Sano, H.; Noguchi, T.; Tanatani, A.; Miyachi, H.; Hashimoto, Y. N-phenylphthalimide-type cyclooxygenase (COX) inhibitors derived from thalidomide: Substituent effects on subtype selectivity. Chem. Pharm. Bull. (Tokyo), 2004, 52(8), 1021-1022. doi: 10.1248/cpb.52.1021 PMID: 15305008Okunrobo, L.O.; Usifoh, C.O.; Okpo, S.O. Reactions of phthalimides with 1-methylethylamine: Analgesic and anti-inflammatory properties of resulting carboxamides. Pak. J. Pharm. Sci., 2006, 19(1), 34-38. PMID: 16632450Rasika, A.; Pophale Meenakshi Deodhar, N. Synthesis and evaluation of novel phthalimide derivatives as analgesic and antiinflammatory agents. Pharma Chem., 2010, 2(1), 185-193.Duarte, C.D.; Tributino, J.L.M.; Lacerda, D.I.; Martins, M.V. AlexandreMoreira, MS.; Dutra, F. Synthesis, pharmacological evaluationand electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl Nacyl hydrazone derivatives: Discovery ofLASSBio-881, a new ligand of cannabinoid receptors. Bioorg. Med. Chem., 2007, 15, 2421-2433. doi: 10.1016/j.bmc.2007.01.013 PMID: 17275312Todeschini, A.R.; de Miranda, A.L.P.; da Silva, K.C.M.; Parrini, S.C.; Barreiro, E.J. Synthesis and evaluation of analgesic, antiinflammatory and antiplatelet properties of new 2-pyridylarylhydrazone derivatives. Eur. J. Med. Chem., 1998, 33(3), 189-199. doi: 10.1016/S0223-5234(98)80008-1Fraga, A.G.M.; Rodrigues, C.R.; de Miranda, A.L.P.; Barreiro, E.J.; Fraga, C.A.M. Synthesis and pharmacological evaluation of novel heterotricyclic acylhydrazone derivatives, designed as PAF antagonists. Eur. J. Pharm. Sci., 2000, 11(4), 285-290. doi: 10.1016/S0928-0987(00)00102-0 PMID: 11033071Silva, G.A.; Costa, L.M.M.; Brito, F.C.F.; Miranda, A.L.P.; Barreiro, E.J.; Fraga, C.A.M. New class of potent antinociceptive and antiplatelet 10H-phenothiazine-1-acylhydrazone derivatives. Bioorg. Med. Chem., 2004, 12(12), 3149-3158. doi: 10.1016/j.bmc.2004.04.009 PMID: 15158783Noguchi, T.; Shimazawa, R.; Nagasawa, K.; Hashimoto, Y. Thalidomide and its analogues as cyclooxygenase inhibitors. Bioorg. Med. Chem. Lett., 2002, 12(7), 1043-1046. doi: 10.1016/S0960-894X(02)00084-7 PMID: 11909713Iman, M.; Shafaroodi, H.; Davood, A.; Abedini, M.; Pishva, P.; Taherkhani, M.; Dehpour, A.; 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(37), 5760-5766. doi: 10.2174/1381612822666160701072127 PMID: 27396602Banarouei, N.; Davood, A.; Shafaroodi, H.; Saeedi, G.; Shafiee, A. N-arylmethylideneaminophthalimide: Design, synthesis and evaluation as analgesic and anti-inflammatory agents. Mini Rev. Med. Chem., 2019, 19(8), 679-687. doi: 10.2174/1389557518666180424101009 PMID: 29692241Saadabadi, A.; Kohen, B.; Irandoust, M.; Shafaroodi, H.; Mohammadpour, T.; Rezayat, M.; Davood, A. 2, 5-Disubstituted Phthalimides: Design, synthesis and anticonvulsant activity in scPTZ and MES models. Curr. Computeraided Drug Des., 2018, 14(4), 310-321. doi: 10.2174/1573409914666180516115450 PMID: 29766822Razmi, A.; Zarghi, A.; Arfaee, S.; Naderi, N.; Faizi, M. Evaluation of anti-nociceptive and anti-inflammatory activities of novel chalcone derivatives. Iran. J. Pharm. Res., 2013, 12(Suppl.), 153-159. PMID: 24250683Valipour, M.; Davaji, I.; Abedi, N.; Rajabi, M.; Küçükkılınç, T.T.; Ayazgök, B.; Irannejad, H. Synthesis and biological assessment of 2-hydroxyiminoethanones as anti-inflammatory and β-amyloid aggregation inhibitors. Iran. J. Pharm. Res., 2019, 18(3), 1288-1298. PMID: 32641939Zarghi, A.; Najafnia, L.; Daraee, B.; Dadrass, O.G.; Hedayati, M. Synthesis of 2,3-diaryl-1,3-thiazolidine-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors. Bioorg. Med. Chem. Lett., 2007, 17(20), 5634-5637. doi: 10.1016/j.bmcl.2007.07.084 PMID: 17822894Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63. doi: 10.1016/0022-1759(83)90303-4 PMID: 6606682Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R.K.; Goodsell, D. S.; Olson, A. J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comp. Chem., 2009, 30(16), 2785-2791.Sidhu, R.S.; Lee, J.Y.; Yuan, C.; Smith, W.L. Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers. Biochemistry, 2010, 49(33), 7069-7079. doi: 10.1021/bi1003298 PMID: 20669977Duggan, K.C.; Walters, M.J.; Musee, J.; Harp, J.M.; Kiefer, J.R.; Oates, J.A.; Marnett, L.J. Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen. J. Biol. Chem., 2010, 285(45), 34950-34959. doi: 10.1074/jbc.M110.162982 PMID: 20810665