Design, Synthesis and Biological Evaluation of 5-amino-3-aryl-1-(6^'-chloropyridazin-3'-yl)pyrazoles and their Derivatives as Analgesic Agents

Abstract

An efficient and environmental benign solvent-free synthesis of 5-amino-3-aryl-1-(6^'-chloropyridazin-3'-yl)pyrazoles (4a-e) was accomplished by grinding 3-chloro-6-hydrazinopyridazine (2) and β-ketonitriles (3a-e) in the presence of p-toulenesulfonic acid as a catalyst. Subsequently, 6'-chloro group in 4a-e was replaced with cyclic 2° amine derivatives viz. pyrrolidine 5a, piperidine 5b and morpholine 5c to obtain 6a-e, 7a-e, 8a-e respectively. The newly synthesized compounds were characterized by using IR, NMR (¹H and ¹³C), mass spectral studies, elemental analyses. All the synthesized compounds were studied for their docking interaction with target protein 6COX and screened for their in vivo analgesic mode of action against swiss albino mice (animal model) using acetic-acid induced writhing test. Consequently, docking simulations data justifies the potential of synthesized series as an analgesic and very well correlated with in vivo study. Preliminary results revealed that most of the synthesized compounds exhibited moderate to good analgesic activity as compared to reference/standard drug (s) sodium diclofenac and candidates 4d and 7c protrude out as a promising lead for further investigation.

Key words

analgesic drugs - anti-inflammatory drugs - biopharmaceuticals - drug research

Publication History

Received: 24 March 2020

Accepted: 18 May 2020

Article published online:
24 July 2020

• References

• 1 Purnima T, Avinash CT, Viney C. et al. Syntheses, characterization and evaluation of novel 2,6-diarylpiperidin-4-ones as potential analgesic-antipyretic agents. Eur J Med Chem 2014; 82: 439-448
• 2 Vinoth PV, Nalini G, Chidambaranathan N. et al. Evaluation of anti- inflammatory and analgesic activity of tridax procumbenslinnagainst formalin, acetic acid and cfa induced pain models. Int J Pharm & Pharm Sci 2011; 3: 126-130
• 3 Rangappa SK, Kallappa MH, Ramya VS. et al. Analgesic, anti-pyretic and DNA cleavage studies of novel pyrimidine derivatives of coumarin moiety. Eur J Med Chem 2010; 45: 2597-2605
• 4 Ferreira SH, Lorenzetti BH, Devissaguet M. et al. S14080, a peripheral analgesic acting by release of anendogenous circulating opioid-like substance. Br J Pharmacol 1995; 114: 303-308
• 5 Syeda AZ, Syed MT, Afzal Q. et al. Nonsteroidal anti-inflammatory drugs. Professional Med J 2016; 23: 460-466
• 6 Krystyna C, Ewa M, Magdalena BZ. Inhibitors of leukotrienes synthesis: novel agents and their implementation. Drug Research 2016; 73: 843-849
• 7 Sebastian B, Carmen BR, Andreas L. et al. Synthesis and biological evaluation of a class of 5-benzylidene-2-phenyl-thiazolinones as potent 5-lipoxygenase inhibitors. Bioorg & Med Chem 2012; 20: 3575-3583
• 8 Chambon JP, Feltz P, Heaulme M. et al. An arylaminopyridazine derivative of gamma-aminobutyric acid (GABA) is a selective and competitive antagonist at the GABA_A receptor site. Proc Natl Acad Sci 1985; 82: 1832-1836
• 9 Takaya M, Sato M, Terashima K. et al. A new nonsteroidal analgesic-anti-inflammatory agent. Synthesis and activityof 4-Ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone and related compounds. J Med Chem 1979; 22: 53-58
• 10 Asif M, Singh A. , Lakshmayya A brief review on triazin-pyridazinones: Synthesis and biological activities. Brazil. J Pharm Sci 2013; 49: 903-909
• 11 Asif M. Overview on emorfazone and other related 3(2H) pyridazinone Analogues displaying analgesic and anti-Inflammatory activity. Ann Med Chem Res 2014; 1: 1004
• 12 Tkachenko PV, Tkachenko OV, Netosova KY. et al. Products of interaction of substituted 5-aminopyrazoles and α-haloketones as potential pharmaceutical agents. Visnik Farmacii 2017; 91: 3-9
• 13 Mark CB, Terence D, Matthew CD. et al. Microwave-assisted synthesis of 5-aminopyrazol-4-yl ketones and the p38MAPK inhibitor RO3201195 for study in Werner syndrome cells. Bioorg Med Chem Lett 2008; 18: 3745-3748
• 14 Bhatt A, Singh RK, Kant R. Discovery of novel pyrazoles as potent antimicrobial and antimalarial agents. Der Pharm Lett 2016; 8: 182-187
• 15 dos Santos FV, Leon LL, Canto-Cavalheiro MM. et al. Effectiveness of novel 5-(5-amino-1-aryl-1H-tetrazole derivatives against promastigotes and amastigotes of leishmania amanzonensis. Chem Biol Drug Des 2014; 83: 272-277
• 16 Mizuhara T, Kato T, Hirari A. et al. Structure-activity relationship study of phenylpyrazole derivatives as a novel class of anti-HIV agents. Bioorg Med Chem Lett 2013; 23: 4557
• 17 Kordik CP, Luo C, Zanoni BC. et al. Pyrazolecarboxamide human neuropeptide Y5 receptor ligands with in vivo antifeedant activity. Bioorg Med Chem Lett 2001; 11: 2287-2290
• 18 Bakr RB, Azouz AA, Adellatif KRA. Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of new 1-phenylpyrazolo[3,4-d]pyrimidine derivatives. J Enzyme Inhib Med Chem 2016; 31: 6-12
• 19 Jagdamba D, Moquin RV, Dyckman AJ. et al. 5-aminopyrazoles as potent and selective p38α inhibitors. Bioorg Med Chem Lett 2010; 20: 6886-6889
• 20 Burcu CE, Maria TN, Luis L. et al. Synthesis of 1,5-diarylpyrazol-3-propanoic acids towards inhibition of cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4 formation. Arzneimittelforschung 2010; 60: 497-505
• 21 Burcu C, Susann L, Yagmur O. et al. Pyrazol-3-propanoic acid derivatives as novel inhibitors of leukotriene biosynthesis in human neutrophils. Eur J Med Chem 2011; 46: 5021-5033
• 22 Aggarwal R, Bansal A, Rozas I. et al. p-Toluenesulfonic acid-catalyzed solvent-free synthesis and biological evaluation of new 1-(4′,6′-dimethylpyrimidin-2′-yl)-5-amino-4H-3-arylpyrazole derivatives. Med Chem Res 2014; 23: 1454-1464
• 23 Mamta, Aggarwal R, Jessie S, Sadana R. Synthesis and cytotoxic evaluation of some new 1-(6-chloropyridazin-3-yl)-3-H/alkyl-4-phenyl-1H-pyrazol-5-amines and their derivatives. Indian J Het Chem 2016; 26: 59-68
• 24 Aggarwal R, Kumar V, Gupta KG. et al. Synthesis of some new 3,5-diamino-4-(4'-fluorophenylazo)-1-aryl/heteroarylpyrazoles as antimicrobial agents. Med Chem Res 2013; 22: 3566-3573
• 25 Aggarwal R, Kumar V, Bansal A. et al. Multi-component solvent-free versus stepwise solvent mediated reactions: Regiospecific formation of 6-trifluoromethyl and4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridines. J Fluor Chem 2012; 140: 31-37
• 26 Aggarwal R, Rani C, Kumar R. et al. Synthesis of new bi(pyrazolo[1,5-a]pyrimidinyl)-7-one derivatives from dehydroacetic acid and its analogues as antibacterial agents. Arkivoc 2014; 2: 120-134
• 27 Aggarwal R, Singh G, Kumar S. et al. Preparation of 4,7-Dihydro-1H -pyrazolo[3,4-b]pyridine-5-nitriles in a multicomponent domino process. Chem Select 2016; 1: 5990-5994
• 28 Aggarwal R, Singh G, Kaushik P. et al. Molecular docking design and one-pot expeditious synthesis of novel 2,5-diarylpyrazolo[1,5-a]pyrimidin-7-amines as anti-inflammatory agents. Eur J Med Chem 2015; 101: 326-333
• 29 Aggarwal R, Kumar V, Singh G. et al. An NMR and computational study of azolo[a]pyrimidines with special emphasis on pyrazolo[1,5-a]pyrimidines. J Het Chem
• 30 Geza S, Peter D. Studies on pyridazine compounds, X1X[1] Mesylation of 5-aminopyrazoles and their related compounds. Monatshefte Fur Chemie 1989; 120: 131-137
• 31 Mohd S, Rizvi D, Shakil S. et al. A simple click by click protocol to perform docking: AutoDock 4.2 made easy for non-bioinformaticians. Excli 2013; 12: 831-857
• 32 Lacerda BR, de Lima FKC, da Silva LL. et al. Discovery of novel analgesic and anti-inflammatory3-arylamine-imidazo[1,2-a]pyridine symbiotic prototypes. Bioorg Med Chem 2009; 17: 74-84
• 33 Petersen EF, Goddard TD, Huang CC. et al. UCSF-Chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004; 25: 1605-1612
• 34 Anupam GB, Nirupam D, Sushant AS. et al. Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6-diphenyl-1,2,4-triazin–3(2H)-one derivatives bearing 5-substituted 1,3,4-oxadiazole as potential anti-inflammatory and analgesic agents. Eur J Med Chem 2015; 101: 81-95
• 35 Elvidge JA, Pickett JA. Heterocyclic imines and amines. Part X111.1 3,6-Dihydrazinopyridazine and the nature of the reaction between 3,6-dimethoxypyridazine and hydrazine. J Chem Soc Perkin 1972; 1: 1483-1488
• 36 Vinod K, Aggarwal R, Tyagi P. et al. Synthesis and antibacterial activity of some new 1-heteroaryl-5-amino-3H/methyl-4-phenylpyrazoles. Bioorg Med Chem 2006; 14: 1785-1791