New pyrazolone derivatives, synthesis, characterization, and neuroprotective effect against PTZ- induced neuroinflammation in mice

Document Type : Original Article

Authors

1 Department of Pharmaceutical Chemistry, Riphah International University, Islamabad, Pakistan, 44000

2 Department of Pharmacognosy, Riphah International University, Islamabad, Pakistan, 44000

3 Department of Chemistry, University of Manitoba, Canada

4 Department of Pharmacology, Riphah International University, Islamabad, Pakistan, 44000

Abstract

Objective(s): The study was aimed at synthesis of the new derivatives of the pyrazolone nucleus, and their spectroscopic and pharmacological analysis and evaluation. 
Materials and Methods: Three series of compounds, with 2-picolinic acid (I a-d), 3-picolinic acid (II a-d), and 4-picolinic acid (III a-d) were synthesized and characterized by FT-IR, 1HNMR, 13C NMR, elemental, and melting points. The new compounds were then evaluated for their anti-oxidant, anti-inflammatory, and anti-epileptic potential. The hind paw edema model was used to screen anti-inflammatory potential, while the anticonvulsant effect was evaluated by employing the acute model of anti-epileptic activity. The in vivo anti-oxidant potential was determined through glutathione (GSH), glutathione-S-transferase (GST), catalase, and lipid peroxidase enzyme (LPO) assays. The expression of key biomarkers involved in inflammation and neuroprotection, including tumor necrotic factors alpha (TNF-α) and phosphorylated nuclear factor kappa B (NF-κB), was detected through enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. 
Results: The tested compounds showed anti-oxidant potential. The selected compounds exhibited good anti-inflammatory potential. The PTZ-induced elevation of these inflammatory mediators and oxidative stress were ameliorated significantly by the selected compound Ic. Results of molecular analysis (ELISA and Western blot analysis) for potent compound Ic showed a prominent inhibitory effect against neuroinflammatory mediators, including TNF-α and NF-κB. 
Conclusion: It is concluded that the derivative Ic ameliorated PTZ-induced seizures, oxidative stress, and inflammatory cascades by regulating the NF-κB/ TNF-α/ROS pathway.

Keywords


1. Orabi EA, Orabi MAA, Mahross MH, Abdel-Hakim M. Computational investigation of the structure and anti-oxidant activity of some pyrazole and pyrazolone derivatives. J Saudi Chem Soc 2018; 22:705-714.
2. Anderson RC. The chemistry of heterocyclic compounds. pyrazolones, pyrazolidones, and derivatives. J Am Chem Soc 1965; 87:140-141.
3. Ahsan MJ, Khalilullah H, Stables JP, Govindasamy J. Synthesis and anticonvulsant activity of 3a, 4-dihydro-3H-indeno [1, 2-c] pyrazole-2-carboxamide/carbothioamide analogues. J Enzyme Inhib Med Chem 2013; 28:644-650.
4. Brogden RN. Pyrazolone derivatives. Drugs 1986; 32:60-70.
5. Brune K. The early history of non-opioid analgesics. Acute Pain 1997; 1:33-40.
6. Knorr L. Einwirkung von acetessigester auf phenylhydrazin. Ber Deutsch Chem Ges 1883; 16:2597-2599.
7. Abdel-Aziz M, Abuo-Rahma GE-DA, Hassan AA. Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities. Eur J  Med Chem 2009; 44:3480-3487.
8. Khalifa MM, Abdelbaky NA. Synthesis of new imidazolyl acetic acid derivatives with anti-inflammatory and analgesic activities. Arch Pharm Res 2008; 31:419-423.
9. Sun ZQ, Meng FH, Tu LX, Sun L. Myricetin attenuates the severity of seizures and neuroapoptosis in pentylenetetrazole kindled mice by regulating the of BDNFTrkB signaling pathway and modulating matrix metalloproteinase9 and GABAA. Exp Ther Med 2019; 17:3083-3091.
10. McMurray KM, Distler MG, Sidhu PS, Cook JM, Arnold LA, Palmer AA, et al. Glo1 inhibitors for neuropsychiatric and anti-epileptic drug development. Biochem Soc Trans 2014; 42:461-467.
11. Queda F, Calò S, Gwizdala K, Magalhães JD, Cardoso SM, Chaves S, et al. Novel donepezil–arylsulfonamide hybrids as multitarget-directed ligands for potential treatment of alzheimer’s disease. Molecules 2021; 26:1658-1673.
12. Dede F, Karadenizli S, Ozsoy OD, Eraldemir FC, Sahin D, Ates N. Antagonism of adenosinergic system decrease SWD occurrence via an increment in thalamic NFkB and IL-6 in absence epilepsy. J Neuroimmunol 2019; 326:1-8.
13. Singh N, Saha L, Kumari P, Singh J, Bhatia A, Banerjee D, et al. Effect of dimethyl fumarate on neuroinflammation and apoptosis in pentylenetetrazol kindling model in rats. Brain Res Bull 2019 2019; 144:233-245.
14. Wang H, Yan H, Wang K, Wang J. Dynamic regulation effect of long non-coding RNA-UCA1 on NF-kB in hippocampus of epilepsy rats. Eur Rev Med Pharmacol Sci 2017; 21:3113-3119.
15. Bhattacharya A, Derecki NC, Lovenberg TW, Drevets WC. Role of neuro-immunological factors in the pathophysiology of mood disorders. Psychopharmacology 2016; 233:1623-1636.
16. Young I, Woodside J. Anti-oxidants in health and disease. J Clin Pathol 2001; 54:176-186.
17. Nimse SB, Pal D. Free radicals, natural antioxidants, and their reaction mechanisms. RSC Adv 2015; 5:27986-8006.
18. Chen Y, Xiao H, Zheng J, Liang G. Structure-thermodynamics-antioxidant activity relationships of selected natural phenolic acids and derivatives: an experimental and theoretical evaluation. PLoS One 2015; 10:1-20.
19. Wright JS, Johnson ER, DiLabio GA. Predicting the activity of phenolic antioxidants: theoretical method, analysis of substituent effects, and application to major families of antioxidants. J Am Chem Soc 2001; 123:1173-1183.
20. Melov S, Ravenscroft J, Malik S, Gill MS, Walker DW, Clayton PE, et al. Extension of life-span with superoxide dismutase/catalase mimetics. Science 2000; 289:1567-1569.
21. Rajendran P, Nandakumar N, Rengarajan T, Palaniswami R, Gnanadhas EN, Lakshminarasaiah U, et al. Antioxidants and human diseases. Clin Chim Acta 2014; 436:332-347.
22. Sidhaye R, Dhanawade A, Manasa K, Aishwarya G. Synthesis, antimicrobial and antimycobacterial activity of nicotinic acid hydrazide derivatives. Int J Curr Pharm Res 2011; 1:135-139.
23. Eldehna ME, Fares M, Abdel-Aziz MM, Abdel Aziz HA.
Design, Synthesis and Antitubercular Activity of Certain Nicotinic
Acid Hydraziides. Molecules 2015; 20: 8800-8815.
24. Patel JB, Sen DJ. Synthesis and biological evaluation of some novel substituted thiazolidine and pyrazolone derivatives. Asian J Chem 2012; 5:901-906.
25. Hasan SR, Hossain MM, Akter R, Jamila M, Mazumder MEH, Rahman S. DPPH free radical scavenging activity of some Bangladeshi medicinal plants. J Med Plants Res 2009; 3:875-879.
26. Li Y-C, Xian Y-F, Ip S-P, Su Z-R, Su J-Y, He J-J, et al. Anti-inflammatory activity of patchouli alcohol isolated from Pogostemonis herba in animal models. Fitoterapia 2011; 82:1295-1301.
27. Blakaj DM, McConnell KJ, Beveridge DL, Baranger AM. Molecular dynamics and thermodynamics of protein− RNA interactions: mutation of a conserved aromatic residue modifies stacking interactions and structural adaptation in the U1A− stem loop 2 RNA complex. J Am Chem Soc 2001; 123:2548-2551.
28. Rana I, Khan N, Ansari MM, Shah FA, ud Din F, Sarwar S, et al. Solid lipid nanoparticles-mediated enhanced antidepressant activity of duloxetine in lipopolysaccharide-induced depressive model. Colloids Surf B Biointerfaces 2020; 194:111209-111249.
29. Al Kury LT, Zeb A, Abidin ZU, Irshad N, Malik I, Alvi AM, et al. Neuroprotective effects of melatonin and celecoxib against ethanol-induced neurodegeneration: A computational and pharmacological approach. Drug Des Devel  Ther 2019; 13:2715-2727.
30. Khan A, Shal B, Naveed M, Shah FA, Atiq A, Khan NU, et al. Matrine ameliorates anxiety and depression-like behaviour by targeting hyperammonemia-induced neuroinflammation and oxidative stress in CCl4 model of liver injury. Neurotoxicology 2019; 72:38-50.
31. Hadwan MH. Simple spectrophotometric assay for measuring catalase activity in biological tissues. BMC Biochem 2018; 19:7-15.
32. Irshad N, Khan A-u, Iqbal MS. Antihypertensive potential of selected pyrimidine derivatives: explanation of underlying mechanistic pathways. Biomed Pharmacother 2021; 139:111567-111582.
33. Anwar T, Nadeem H, Sarwar S, Naureen H, Ahmed S, Khan A, et al. Investigation of antioxidant and anti‐nociceptive potential of isoxazolone, pyrazolone derivatives, and their molecular docking studies. Drug Dev Res 2020; 81:893-903.
34. Surati KR, Sathe PA. Schiff base pyrazolone complexes of iron (III): synthesis, characterization, antimicrobial and antioxidant activity. Med Chem Res 2016; 25:2742-2751.
35. K Okla M, Alamri SA, Alaraidh IA, AL‐ghamdi AA, Soufan WH, Allam AA, et al. Synthesis of pyrazolin‐5‐one derivatives clubbed with thiazole and/or thiadiazole and evaluation of their antioxidant and cytotoxic activities. ChemistrySelect 2019; 4:11735-11739.
36. Minnelli C, Laudadio E, Galeazzi R, Rusciano D, Armeni T, Stipa P, et al. Synthesis, characterization and antioxidant properties of a new lipophilic derivative of edaravone. Antioxidants 2019; 8:258-572.
37. Vallés SL, Blanco AM, Pascual M, Guerri C. Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol 2004; 14:365-371.
38. Alfonso-Loeches S, Pascual-Lucas M, Blanco AM, Sanchez-Vera I, Guerri C. Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci 2010; 30:8285-8295.