Pyrrolopyrazoles: Synthesis, Evaluation and Pharmacological Screening as Antidepressant Agents

Author(s): Samar S. Fatahala*, Shahira Nofal, Eman Mahmoud, Rania H. Abd El-hameed

Journal Name: Medicinal Chemistry

Volume 15 , Issue 8 , 2019

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Graphical Abstract:


Background: Pyrroles and fused pyrroles are of great interest as biologically active compounds, among these activities; antidepressant activity is of special concern.

Objective: Synthesis of a series of pyrrolopyrazoles and their pyrimidine derivatives and their characterization using spectral data to be monitored for antidepressant activity using behavioral techniques.

Methods: A control group was administered the vehicle i.p., positive control group received fluoxetine as standard and all other groups were administered the tested compounds. The groups were subjected to tail suspension test (TST) to determine the antidepressant activity compared with fluoxetine as a standard drug. The compounds exhibiting antidepressant activity were then used to analyze changes in serotonin (5HT) level in the brain of albino mice.

Results: TST results showed that both pyrazoles and pyrazolopyrimidines derivatives exhibit promising anti-depressant activity.

Conclusion: Compounds [pyrazoles & pyrazlopyrimidines] showed promising antidepressant activity possibly mediated by the increased levels of 5HT.

Keywords: Pyrrole, pyrrolopyrazole, pyrazolopyrimidine, synthesis, SAR, anti-depressant assay.

Laursen, T.; Borch, J.; Knudsen, C.; Bavishi, K.; Torta, F.; Martens, H.J.; Silvestro, D.; Hatzakis, N.S.; Wenk, M.R.; Dafforn, T.R.; Olsen, C.E.; Motawia, M.S.; Hamberger, B.; Møller, B.L.; Bassard, J-E. Characterization of a dynamic metabolon producing the defense compound dhurrin in sorghum. Science, 2016, 354(6314), 890-893.
[] [PMID: 27856908]
Pytka, K.; Żmudzka, E.; Lustyk, K.; Rapacz, A.; Olczyk, A.; Gałuszka, A.; Waszkielewicz, A.; Marona, H.; Sapa, J.; Barbara, F. The Antidepressant- and Anxiolytic-like Activities of New Xanthone Derivative with Piperazine Moiety in Behavioral Tests in Mice; Indian Journal of Pharmacology: India, 2016, 286-291.
Krämer, U.M.; Cunillera, T.; Càmara, E.; Marco-Pallarés, J.; Cucurell, D.; Nager, W.; Bauer, P.; Schüle, R.; Schöls, L.; Rodriguez-Fornells, A.; Münte, T.F. The impact of catechol-O-methyltransferase and dopamine D4 receptor genotypes on neurophysiological markers of performance monitoring. J. Neurosci., 2007, 27(51), 14190-14198.
[] [PMID: 18094258]
Kang, S.Y.; Park, E-J.; Park, W-K.; Kim, H.J.; Jeong, D.; Jung, M.E.; Song, K-S.; Lee, S.H.; Seo, H.J.; Kim, M.J.; Lee, M.; Han, H-K.; Son, E-J.; Pae, A.N.; Kim, J.; Lee, J. Arylpiperazine-containing pyrrole 3-carboxamide derivatives targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant. Bioorg. Med. Chem. Lett., 2010, 20(5), 1705-1711.
[] [PMID: 20149649]
Meltzer, H.Y. Role of serotonin in depression. Ann. N. Y. Acad. Sci., 1990, 600, 486-499.
[] [PMID: 2252328]
Deakin, J.F. Depression and 5HT. Int. Clin. Psychopharmacol., 1991, 6(Suppl. 3), 23-28.
[] [PMID: 1806632]
Ressler, K.J.; Nemeroff, C.B. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress. Anxiety, 2000, 12(Suppl. 1), 2-19.
[<2:AID-DA2>3.0.CO;2-4] [PMID: 11098410]
Kumar, L.V.; Naik, P.J.; Chandrasekhar, T.; Reddy, A.B.; Karuna, M.; Penchalaiah, N.; Swamy, G.N. Synthesis, Characterisation of Some Derivatives of 3-[(4-Chlorophenyl) Sulfonyl] Propane Hydrazide, 2012, 4(2), 674-678.
Sapa, J.; Filipek, B.; Kulig, K.; Malawska, B. Antidepressant-like activity of the phenylpiperazine pyrrolidin-2-one derivatives in mice. Pharmacol. Rep., 2011, 63(1), 71-78.
[] [PMID: 21441613]
Patil, P.O.; Bari, S.B. Synthesis, Characterization and Screening for Antidepressant and Anticonvulsant Activity of 4,5-Dihydropyrazole Bearing Indole Derivatives. Arab. J. Chem., 2013, 4-11.
Jammer, S.; Gelman, F.; Lev, O. Applicability of the Rayleigh Equation for Enantioselective Metabolism of Chiral Xenobiotics by Microsomes, Hepatocytes and in-Vivo Retention in Rabbit Tissues. Sci. Rep., 2015, 2016(6), 1-10.
[PMID: 27021918]
Park, D.I.; Dournes, C.; Sillaber, I.; Uhr, M.; Asara, J.M.; Gassen, N.C.; Rein, T.; Ising, M.; Webhofer, C.; Filiou, M.D.; Müller, M.B.; Turck, C.W. Purine and pyrimidine metabolism: Convergent evidence on chronic antidepressant treatment response in mice and humans. Sci. Rep., 2016, 6(August), 35317.
[] [PMID: 27731396]
Napier, S.; Bingham, M. Topics in Medicinal Chemistry, 2009.
Sindhu, T.; Mamatha, A.K. S. R.; Venkateshwarlu, K. Anti-Depressant Activity of Pyrimidine Derivatives in Mice. Hygeia.J.D. Med., 2013, 5(April), 125-130.
Raz, A. Perspectives on the efficacy of antidepressants for child and adolescent depression. PLoS Med., 2006, 3(1)e9
[] [PMID: 16354104]
Osório, F. de L.; Sanches, R.F.; Macedo, L.R.; Santos, R.G.; Maia-de-Oliveira, J.P.; Wichert-Ana, L.; Araujo, D.B.; Riba, J.; Crippa, J.A.; Hallak, J.E. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Br. J. Psychiatry, 2015, 37(1), 13-20.
[] [PMID: 25806551]
Venault, P.; Chapouthier, G. From the behavioral pharmacology of beta-carbolines to seizures, anxiety, and memory. ScientificWorldJournal, 2007, 7, 204-223.
[] [PMID: 17334612]
Osório, F.D.L.; Ribeiro, L.; De Macedo, H.; Quevedo, J.; Alexandre, J.; Crippa, D.S. The Therapeutic Potential of Harmine and Ayahuasca in Depression : Evidence from Exploratory Animal and Human Studies. Ethnopharmacol. Ayahuasca, 2011, 661(2), 75-85.
Traxler, P.M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer, T.; Lydon, N. 4-(Phenylamino)pyrrolopyrimidines: potent and selective, ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase. J. Med. Chem., 1996, 39(12), 2285-2292.
[] [PMID: 8691423]
Wang, S.J. Potential antidepressant LY 367265 presynaptically inhibits the release of glutamate in rat cerebral cortex. Synapse, 2005, 55(3), 156-163.
[] [PMID: 15602751]
Lin, F.; Li, F.; Wang, C.; Wang, J.; Yang, Y.; Yang, L.; Li, Y. Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2Areceptor by in Silico Methods. Molecules, 2017, 22(7)
Jain, K.S.; Chitre, T.S.; Miniyar, P.B.; Kathiravan, M.K.; Bendre, V.S.; Veer, V.S.; Shahane, S.R.; Shishoo, C.J. Biological and Medicinal Significance of Pyrimidines. Curr. Sci., 2006, 90(6), 793-803.
Shapiro, G.; Gainesville, F. Pyrrolopyrimidine Derivatives as NR2B NMDA Receptor Antagonists, 2017.
Mohamed, M.S.; Hussein, W.M.; McGeary, R.P.; Vella, P.; Schenk, G.; Abd El-Hameed, R.H. Synthesis and kinetic testing of new inhibitors for a metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. Eur. J. Med. Chem., 2011, 46(12), 6075-6082.
[] [PMID: 22051063]
Mohamed, M.S.; Ali, S.A.; Abdelaziz, D.H.A.; Fathallah, S.S. Synthesis and evaluation of novel pyrroles and pyrrolopyrimidines as anti-hyperglycemic agents. BioMed Res. Int., 2014, 2014249780
[] [PMID: 25054134]
Hussein, W.M.; Fatahala, S.S.; Mohamed, Z.M.; McGeary, R.P.; Schenk, G.; Ollis, D.L.; Mohamed, M.S. Synthesis and kinetic testing of tetrahydropyrimidine-2-thione and pyrrole derivatives as inhibitors of the metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. Chem. Biol. Drug Des., 2012, 80(4), 500-515.
[] [PMID: 22738437]
Mohamed, M.S.; Kamel, R. Abd El-hameed, R. H. Evaluation of the Anti-Inflammatory Activity of Some Pyrrolo[2,3-d]Pyrimidine Derivatives. Med. Chem. Res., 2012, 22(5), 2244-2252.
Fatahala, S.S.; Mahgub, S.; Taha, H.; Abd-El Hameed, R.H. Synthesis and evaluation of novel spiro derivatives for pyrrolopyrimidines as anti-hyperglycemia promising compounds. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 809-817.
[] [PMID: 29708461]
Kwon, S.; Lee, B.; Kim, M.; Lee, H.; Park, H-J.; Hahm, D-H. Antidepressant-like effect of the methanolic extract from Bupleurum falcatum in the tail suspension test. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2010, 34(2), 265-270.
[] [PMID: 19932727]
Steru, L.; Chermat, R.; Thierry, B.; Simon, P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl.), 1985, 85(3), 367-370.
[] [PMID: 3923523]
Cunha, M.P.; Machado, D.G.; Bettio, L.E.B.; Capra, J.C.; Rodrigues, A.L.S. Interaction of zinc with antidepressants in the tail suspension test. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2008, 32(8), 1913-1920.
[] [PMID: 18824054]
Aslam, M. Tail Suspension Test to Evaluate the Antidepressant Activity of Experimental Drugs. Bangladesh J. Pharmacol., 2016, 11(2), 292-294.
Zagrodzka, J.; Romaniuk, A.; Wieczorek, M.; Boguszewski, P. Bicuculline administration into ventromedial hypothalamus: effects on fear and regional brain monoamines and GABA concentrations in rats. Acta Neurobiol. Exp. (Warsz.), 2000, 60(3), 333-343.
[PMID: 11016075]
Fatahala, S.S.; Shalaby, E.A.; Kassab, S.E.; Mohamed, M.S. A promising anti-cancer and anti-oxidant agents based on the pyrrole and fused pyrrole: synthesis, docking studies and biological evaluation. Anticancer. Agents Med. Chem., 2015, 15(4), 517-526.
[] [PMID: 25929576]
Fatahala, S.S.; Mohamed, M.S.; Youns, M.; Abd-El Hameed, R.H. Synthesis and Evaluation of Cytotoxic Activity of Some Pyrroles and Fused Pyrroles. Anticancer. Agents Med. Chem., 2017, 17(7), 1014-1025.
[] [PMID: 28042776]
Said Fatahala, S.; Hasabelnaby, S.; Goudah, A.; Mahmoud, G.I.; Helmy Abd-El Hameed, R. Pyrrole and Fused Pyrrole Compounds with Bioactivity against Inflammatory Mediators. Molecules, 2017, 22(3), 1-18.
[] [PMID: 28304349]
Mohamed, M.S.; Abd El-Hameed, R.H.; Sayed, A.I. Synthesis Strategies and Biological Value of Pyrrole and Pyrrolopyrimidine. J. Adv. Pharm. Educ. Res., 2017, 1(1), 1-24.
Abdel-Mohsen, S.A. Synthesis, Reactions and Antimicrobial Activity of 2-Amino-4-(8-Quinolinol-5-Yl)-1-(p-Tolyl)-Pyrrole-3-Carbonitrile. Bull. Korean Chem. Soc., 2005, 26(5), 719-728.
Al-Matar, H.M.; Khalil, K.D.; Al-Dorri, D.M.; Elnagdi, M.H. Efficient routes to pyrazolo[3,4-e][1,2,4]triazines and a new ring system: [1,2,4]triazino[5,6-d][1,2,3]triazines. Molecules, 2010, 15(5), 3302-3310.
[] [PMID: 20657480]
Hitzemann, R. Animal models of psychiatric disorders and their relevance to alcoholism. Alcohol Res. Health, 2000, 24(3), 149-158.
[PMID: 11199284]
Sherman, A.D.; Petty, F. Additivity of neurochemical changes in learned helplessness and imipramine. Behav. Neural Biol., 1982, 35(4), 344-353.
[] [PMID: 6299264]
Cryan, J.F.; Mombereau, C.; Vassout, A. The tail suspension test as a model for assessing antidepressant activity: review of pharmaco-logical and genetic studies in mice. Neurosci. Biobehav. Rev., 2005, 29(4-5), 571-625.
[] [PMID: 15890404]

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Year: 2019
Published on: 18 November, 2019
Page: [911 - 922]
Pages: 12
DOI: 10.2174/1573406414666181108090321
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