Design and Synthesis of Some Enaminonitrile Derivatives of Antipyrine as Potential Novel Anti-Inflammatory and Analgesic Agents


The starting (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbon-hydrazonoyl dicyanide (2) was used as a key intermediate for the syntheses of novel acyclic enaminonitriles 3-10. The newly synthesized compounds were characterized by elemental analyses and spectral data (IR, 1H NMR, 13C NMR and mass spectra). The anti-inflammatory activity data indicated that many of tested compounds protected rats from carrageenan-induced inflammation, and tested compounds 3, 4, 9 and 10 were the most potent among tested compounds. The analgesic activity was determined by the hot plate test (central analgesic activity) and acetic acid induced writhing assay. The results revealed that compounds 3, 4, 9, and 10 exhibited significant activity. However, compound 10 proved to have better or equivalent activities in comparison to the reference drug.

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Fadda, A. and Elattar, K. (2015) Design and Synthesis of Some Enaminonitrile Derivatives of Antipyrine as Potential Novel Anti-Inflammatory and Analgesic Agents. Journal of Biosciences and Medicines, 3, 114-123. doi: 10.4236/jbm.2015.311015.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Madkour, H.M.F., Afify, A.A.E., Abdalha, A.A., Elsayed, G.A. and Salem, M.S. (2009) Synthetic Utility of Enaminonitrile Moiety in Heterocyclic Synthesis: Synthesis of Some New Thienopyrimidine. Phosphorus, Sulfur, and Silicon and the Related Elements, 184, 719-732.
[2] Shaaban, M.R., Saleh, T.S. and Farag, A.M. (2009) Synthesis and Antimicrobial Evaluation of New Thiophene and 1,3,4-Thiadiazole Derivatives. Heterocycles, 78, 151-159.
[3] Elkholy, A., Al-Qalaf, F. and Elnagdi, M.H. (2008) Regio-Orientation in Condensation of Aminopyrazoles with 1,3-Difunctional Reagents: Synthesis of New Pyrazolo[1,5-a]Pyrimidines; Pyrazolo[3,4-d]Pyridazines and 2,4-Dihydro- pyrano[2,3-c]Pyrazoles. Arkivoc (Archive for Organic Chemistry), 2008, 124-131.
[4] Dannhardt, G. and Kiefer, W. (2001) Cyclooxygenase Inhibitors—Current Status and Future Prospects. European Journal of Medicinal Chemistry, 36, 109-126.
[5] Sondhi, S.M., Singhal, N., Johar, M., Reddy, B.S.N. and Lown, J.W. (2002) Heterocyclic Compounds as Inflammation Inhibitors. Current Medicinal Chemistry, 9, 1045-1074.
[6] Bertolini, A., Ottani, A. and Sandrini, M. (2002) Selective COX-2 Inhibitors and Dual Acting Anti-Inflammatory Drugs. Current Medicinal Chemistry, 9, 1033-1043.
[7] Bekhit, A.A. and Abdel-Azeim, T. (2004) Design, Synthesis and Biological Evaluation of Some Pyrazole Derivatives as Anti-Inflammatory-Antimicrobial Agents. Bioorganic & Medicinal Chemistry, 12, 1935-1945.
[8] Shamroukh, A.H., Zaki, M.E.A., Morsy, E.M.H., Abdel-Motti, F.M. and Abdel-Megeid, F.M.E. (2007) Synthesis, Isomerization, and Antimicrobial Evaluation of Some Pyrazolopyranotriazolopyrimidine Derivatives. Archiv der Pharmazie, 340, 345-351.
[9] Kuettel, S., Zambon, A., Kaiser, M., Brun, R., Scapozza, L. and Perozzo, R. (2007) Synthesis and Evaluation of Antiparasitic Activities of New 4-[5-(4-Phenoxyphenyl)-2H-Pyrazol-3-yl]Morpholine Derivatives. Journal of Medicinal Chemistry, 50, 5833-5839.
[10] Yan, R.-Z., Liu, X.-Y., Xu, W.-F., Pannecouque, C., Witvrouw, M. and De Clercq, E. (2006) Synthesis and Anti-HIV Evaluation of the Novel 2-(m-Chlorobenzyl)-4-Substituted-7-Methyl-1,1,3-Trioxo-Pyrazolo[4, 5-e][1,2,4]Thiadiazines. Archives of Pharmacal Research, 29, 957-962.
[11] Diana, P., Carbone, A., Barraja, P., Martorana, A., Gia, O., Dalla Via, L. and Cirrincione, G. (2007) 3,5-Bis(3’-indolyl)-pyrazoles, Analogues of Marine Alkaloid Nortopsentin: Synthesis and Antitumor Properties. Bioorganic & Medicinal Chemistry Letters, 17, 6134-6137.
[12] Comber, R.N., Gray, R.J. and Secrist, J.A. (1991) Acyclic Analogues of Pyrazofurin: Syntheses and Antiviral Evaluation. Carbohydrate Research, 216, 441-452.
[13] Ali, A.M., Saber, G.E., Mahfouz, N.M., El-Gendy, M.A., Radwan, A.A. and Hamid, M.A.E. (2007) Synthesis and Three-Dimensional Qualitative Structure Selectivity Relationship of 3,5-Disubstituted-2,4-thiazolidinedione Derivatives as COX2 Inhibitors. Archives of Pharmacal Research, 30, 1186-1204.
[14] Mahran, A.M. and Hassan, N.A. (2006) A One-Step Synthesis and Antimicrobial Activities of New Substituted Dihydro-1,3,4-thiadiazoles. Archives of Pharmacal Research, 29, 46-49.
[15] Fadda, A.A., Bondock, S., Rabie, R. and Etman, H.A. (2008) Synthesis and Antimicrobial Activity of Some New Heterocycles Incorporating Antipyrine Moiety. European Journal of Medicinal Chemistry, 43, 2122-2129.
[16] Fadda, A.A., Bondock, S. and Rabie, R. (2008) Heterocyclic Synthesis with 4-Benzoyl-1-cyanoacetyl-thiosemicarbazide: Selective Synthesis of Some Thiazole, Triazole, Thiadiazine, Pyrrylthiazole and Pyrazolo[1,5-a]triazine Derivatives. Monatshefte für Chemie, 139, 153-159.
[17] Fadda, A.A. and Youssif, E.H.E. (2011) Synthesis of Some New Chromene Derivatives, Part (VI). Synthetic Communications, 41, 677-694.
[18] Fadda, A.A., Bondock, S. and Tarhoni, A.-G. (2011) Recent Progress in the Synthesis and Applications of Heterocycles Derived from Enaminonitriles. Current Organic Chemistry, 15, 753-781.
[19] Elattar, K.M., Fadda, A.A. and Fouda, A.S. (2012) Synthesis of Polyfunctionalized Bioactive Corrosion Inhibitors. LAP Lambert Academic Publishing GmbH & Co. KG, VDM Verlagsservicegesellschaft mbH, Saarbrücken.
[20] Fadda, A.A., Etman, H.A., El-Seidy, M.Y. and Elattar, K.M. (2012) Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis of Some New Pyrazole, Pyridine, and Pyrimidine Derivatives. Journal of Heterocyclic Chemistry, 49, 774-781.
[21] Fadda, A.A. and Elattar, K.M. (2012) Synthesis of Novel Azo Disperse Dyes Derived from 4-Aminoantipyrine and Their Applications to Polyester Fabrics. American Journal of Organic Chemistry, 2, 52-57.
[22] Fadda, A.A. and Elattar, K.M. (2013) Efficient and Convenient Route for the Synthesis of Some New Antipyrinyl Monoazo Dyes: Application to Polyester Fibers and Biological Evaluation. Journal of Chemistry, 2013, Article ID: 928106.
[23] Fadda, A.A. and Elattar, K.M. (2014) Utility of Enaminonitriles in Heterocyclic Synthesis: Synthesis of Some New Azepine, Azocine and Pyrroldione Derivatives. Journal of Heterocyclic Chemistry, 51, 1697-1704.
[24] El-Haddad, M.N. and Elattar, K.M. (2015) Synthesis, Characterization and Inhibition Effect of New Antipyrinyl Derivatives on Mild Steel Corrosion in Acidic Solution. International Journal of Industrial Chemistry, 6, 105-117.
[25] El-Haddad, M.N. and Elattar, K.M. (2013) Role of Novel Oxazocine Derivative as Corrosion Inhibitor for 304 Stainless Steel in Acidic Chloride Pickling Solutions. Research on Chemical Intermediates, 39, 3135-3149.
[26] Fouda, A.S. and Elattar, K.M. (2012) Corrosion Inhibition of Carbon Steel by New Enaminonitrile Derivatives in HCl Solution. Journal of Scientific and Industrial Research, 71, 690-698.
[27] Krystof, V., Cankar, P., Fryaová, I., Slouka, J., Kontopidis, G., Dzubák, P., Hajdúch, M., Srovnal, J., de Azevedo Jr., W.F., Orság, M., Paprskárová, M., Rolcík, J., Látr, A., Fischer, P.M. and Strnad, M. (2006) 4-Arylazo-3,5-diamino-1H-pyrazole CDK Inhibitors: SAR Study, Crystal Structure in Complex with CDK2, Selectivity, and Cellular Effects. Journal of Medicinal Chemistry, 49, 6500-6509.
[28] Abu-Hashem, A.A., Gouda, M.A. and Badria, F.A. (2010) Synthesis of Some New Pyrimido[2’,1’:2,3]thiazolo[4,5-b]-Quinoxaline Derivatives as Anti-Inflammatory and Analgesic Agents. European Journal of Medicinal Chemistry, 45, 1976-1981.
[29] El-Gazzar, A.B.A., Youssef, M.M., Youssef, A.M.S., Abu-Hashem, A.A. and Badria, F.A. (2009) Design and Synthesis of Azolopyrimidoquinolines, Pyrimidoquinazolines as Anti-Oxidant, Anti-Inflammatory and Analgesic Activities. European Journal of Medicinal Chemistry, 44, 609-624.
[30] Olfert, E.D., Cross, B.M. and McWilliam, A.A., Eds. (1993) Guide to the Care and Use of Experimental Animals. 2nd Edition, Canadian Council on Animal Care, Ottawa.
[31] Winter, C.A., Risley, E.A. and Nuss, G.W. (1962) Carrageenin-Induced Edema in Hind Paw of the Rat as an Assay for Antiinflammatory Drugs. Experimental Biology and Medicine, 111, 544-547.
[32] Mino, J., Moscatelli, V., Hnatyszyn, O., Gorzalczany, S., Acevedo, C. and Ferraro, G. (2004) Antinociceptive and Antiinflammatory Activities of Artemisia copa Extracts. Pharmacological Research, 50, 59-63.
[33] Turner, R.A. (1965) Analgesic. In: Turner, R.A., Ed., Screening Methods in Pharmacology, Academic Press, London, 100.
[34] Collier, H.D.J., Dinnin, L.C., Johnson, C.A. and Schneider, C. (1968) The Abdominal Constriction Response and Its Suppression by Analgesic Drugs in the Mouse. British Journal of Pharmacology and Chemotherapy, 32, 295-310.

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