Investigation of Anti-inflammatory and Antioxidant Activities of Promising 1,4,5-Trisubstituted Pyrazoles Derivatives of Chalcone Ditosylates
Abstract
Patients suffering from chronic pain and inflammatory disorders need novel COX-2 inhibitors to be developed with minimum toxicity to the kidneys, heart, and gastrointestinal tract and with excellent anti-inflammatory activity. The current study centers on an array of 1,4,5-trisubstituted pyrazoles produced via the reaction of ditosylates of chalcones with hydrochloride salt of phenylhydrazine. Chalcone was reacted with HTIB to produce a variety of derivatives of α, β chalcone ditosylates. Phenylhydrazine hydrochloride treatment of these chalcone ditosylates produced distinct 1,4,5-trisubstituted pyrazoles. The conversion process is mediated by 1,2-aryl migrations. IR, 1NMR, and elemental analysis were used to characterize the compounds after they had been purified by recrystallization. Using ascorbic acid as a reference, the DPPH (1,1-diphenyl-2-picrylhydrazyl) technique was used to assess the compounds' in vitro antioxidant activity. The paw edema technique caused by Carrageenan was utilized to assess the compounds' in vivo anti-inflammatory properties. The standard medication used was diclofenac sodium. A plethysmograph was used to measure the volume of the rats' paws. When compared to the standard, the compounds V5D5PH5 and V7D7PH7 showed modest antioxidant activity. When the synthetic pyrazoles were examined for their in vivo anti-inflammatory properties, substances V4D4PH4 and V7D7PH7 outperformed the reference. Here, we attempted to create new, safe, and effective drugs for the treatment of inflammatory disorders and pain by utilizing synthetic pyrazole moiety derivatives. Simple experimentation is used in the proposed study to improve pharmacological activity and yields. In the near future, chalcone ditosylate derivatives will be a powerful tool for selective modification.
Keywords:
Chalcone, Substituted Pyrazole, Koser’s reagent, Anti-inflammatory, AntioxidantDOI
https://doi.org/10.25004/IJPSDR.2024.160408References
Cristiano S. Revisiting the Structure and Chemistry of 3(5)-Substituted Pyrazoles. Molecules. 2020; 25:42. Available from: doi: 10.3390/molecules25010042
Sharanabasappa Patil B. Medicinal Significance of Pyrazole Analogues: A Review. Journal of Pharmaceutical Sciences and Research. 2020;12(3);402-404. Available from: doi.org/10.53730/ijhs.v6nS2.5177
Aziz H, Zahoor AF, Shahzadi I and Irfan A. Recent synthetic methodologies towards the synthesis of pyrazoles. Polycyclic Aromatic Compounds. 2021;41(4):698-720 Available from: DOI:10.1080/10406638.2019.1614638
Mullins ST. Five-membered heterocyclic compounds with two nitrogen atoms in the ring. Supplements to the of Rodd's Chemistry of Carbon Compounds, A Modern Comprehensive Treatise, 2nd Edition, 4, 1-93 (1975)
Zhang S, Gao Z, Lan D, Jia Q, Liu N, Zhang J, Kou K. Recent Advances in Synthesis and Properties of Nitrated Pyrazoles Based Energetic Compounds. Molecules. 2020; 25(3475): 01-42. Available from: https://doi.org/10.3390/molecules25153475
Ahmed M, Sophy E and Reheim MA. Synthesis of Some New 1, 3, 4-Oxadiazole, Pyrazole, and Pyrimidine Bearing Thienopyrazole Moieties. Mini-Reviews in Medicinal Chemistry. 2020; 17(8):661- 670. Available from: DOI: 10.2174/1570179417999200730215318
Zeinab AM, Alshehrei F, Mohie EMZ, Thoraya AF and Abdallah MA. Synthesis of Novel Bis-pyrazole Derivatives as Antimicrobial Agents. Mini-Reviews in Medicinal Chemistry. 2019; 19(15):1276- 1290. Available from: DOI: 10.2174/1389557519666190313095545
Hassana AS, Moustafab GO, Morsya NM , Abdoud AM and Hafez TS. Design, Synthesis and Antibacterial Activity of N-Aryl-3- (arylamino)-5-(((5-substituted furan-2-yl)methylene)amino)-1Hpyrazole-4- carboxamide as Nitrofurantoin Analogues. Egypt. J. Chem. 2020;63(11):4469- 4481. Available from: DOI: 10.21608/EJCHEM.2020.26158.2525
Awasthi SK, Mishra N, Kumar B, Sharma M, Bhattacharya A, Mishra LC, Bhasin VK. Potent antimalarial activity of newly synthesized substituted chalcone analogs in vitro. Med. Chem. Res. 2019;18:407-420. Available from: DOI:10.1007/s00044-008-9137-9
Szabo G, Fischer J, Kis-Varga A, Gyires K. New Celecoxib derivatives as anti-inflammatory agents. J Med Chem. 2008;51:142–147. Available from: DOI: 10.1021/jm070821f
Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammtory drugs. N Engl J Med. 1999;340:1888–1899. Available from: DOI: 10.1056/NEJM199906173402407
Nakamura T, Sato M, Kakinuma H, et al. Pyrazole and isoxazole derivatives as new, potent, and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors. J Med Chem. 2003;46:5416–27. Available from: DOI: 10.1021/jm020557k
Cheng H, DeMello KML, Li J, et al. Synthesis and SAR of heteroaryl-phenyl-substituted pyrazole derivatives as highly selective and potent canine COX-2 inhibitors. Bioorg Med Chem Lett. 2006;16:2076–80. Available from: DOI: 10.1016/j.bmcl.2006.01.059
Bekhit AA, Ashour HMA, Ghany YSA, et al. Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents. Eur J Med Chem. 2008;43:456–63. Available from: DOI: 10.1016/j.ejmech.2007.03.030
El-Sayed MA-A, Abdel-Aziz NI, Abdel-Aziz AAM, et al. Design, synthesis, and biological evaluation of substituted hydrazone and pyrazole derivatives as selective COX-2 inhibitors: molecular docking study. Bioorg Med Chem. 2011;19:3416–24. Available from: DOI: 10.1016/j.bmc.2011.04.027
Nagarapu L, Materi J, Gaikwad HK, et al. Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives. Bioorg Med Chem Lett 2011;21:4138–40. Available from: DOI: 10.1016/j.bmcl.2011.05.105
Ahlstrom MM, Ridderstrom M, Zamora I, Luthman K. CYP2C9 Structure-metabolism relationships: optimizing the metabolic stability of COX-2 inhibitors. J Med Chem. 2007;50:4444–52. Available from: https://doi.org/10.1021/jm0705096
Prakash O, Kumar R, Parkash V. Synthesis and antifungal activity of some new 3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl) chromones. Eur J Med Chem. 2008;43:435–40. Available from: DOI: 10.1016/j.ejmech.2007.04.004
Brough PA, Aherne W, Barril X, et al. 4,5-Diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem. 2008;51:196–218. Available from: DOI: 10.1016/j.ejmech.2007.04.004
Vera-Di Vaio MAF, Freitas ACC, Castro HCA, et al. Synthesis, antichagasic in vitro evaluation, cytotoxicity assays, molecular modeling and SAR/QSAR studies of a 2-phenyl-3-(1-phenyl-1H-pyrazol-4-yl)-acrylic acid benzylidene-carbohydrazide series. Bioorg Med Chem. 2009;17:295–302. Available from: DOI:10.1016/j.bmc.2008.10.085
Singh P, Paul K, Holzer W. Synthesis of pyrazole-based hybrid molecules: search for potent multidrug resistance modulators. Bioorg Med Chem. 2006;14:5061–71. Available from: DOI: 10.1016/j.bmc.2006.02.046
Hsu TC, Robins RK, Cheng CC. Studies on 4APP: antineoplastic action in vitro. Science. 1956;13:848–68. Available from: DOI: 10.3109/14756366.2013.873037
Storer R, Ashton CJ, Baxter AD, The synthesis and antiviral activity of 4-fluoro-1-β-d-ribofuranosyl-1h-pyrazole-3-carboxamide. Nucleosides, Nucleotides, Nucleic Acids. 1999;18:203–16. Available from: DOI: 10.1080/15257779908043068
Genin MJ, Biles C, Keiser BJ, et al. Novel 1,5-diphenylpyrazole nonnucleoside hiv-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: lead identification and SAR of 3- and 4-substituted derivatives. J Med Chem. 2000;43:1034–40. Available from: DOI: 10.1021/jm990383f
Qiao JX, Pinto DJ, Orwat MJ, et al. Preparation of 1,1-disubstituted cycloalkyl derivatives as factor Xa inhibitors for treating a thromboembolic disorder. PCT Int Appl WO 03 99, 276 (Chem Abstr 2004;140:16722g)
Baraldi PG, Bovero A, Fruttarolo F, et al. New strategies for the synthesis of A3 adenosine receptor antagonists. Bioorg Med Chem. 2003;11:4161–9. Available from: DOI: 10.1016/s0968-0896(03)00484-x
Stamford AW, Wu Y. Preparation of N-(phenyl)pyrazolyl-N′-piperidinylureas as neuropeptide Y Y5 receptor antagonists. PCT Int Appl WO 2004, 5262 (Chem. Abstr. 2004;140:11141. Available from: DOI: 10.3109/14756366.2013.873037
Brown ML, Cheung M, Dickerson SH, et al. Preparation of pyrazolopyrimidines as kinase inhibitors for the treatment of type 2 diabetes. PCT Int Appl WO 2004, 9596 (Chem. Abstr. 2004;140:128436y. Available from: DOI: 10.1021/acsinfecdis.0c00803
Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Eng J Med. 1984;310:563–72. Available from: DOI: 10.1056/NEJM198403013100905
Duma J, Hatoum-Mokdad H, Sibley R, et al. 1-Phenyl-5-pyrazolyl ureas: potent and selective p38 kinase inhibitors. Bioorg Med Chem Lett. 2000;10:2051–4. Available from: DOI: 10.1016/s0960-894x(00)00272-9
Khanna IK, Yu Y, Huff RM, et al. Selective Cyclooxygenase-2 inhibitors: heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents. J Med Chem. 2000;43: 3168–85. Available from: DOI: 10.1021/jm0000719
Abdel-Rahman H.M, Hussien M.A. Synthesis of β-hydroxypropanoic acid derivatives as potential anti-inflammatory, analgesic and antimicrobial agents. Arch Pharm Chem Life Sci. 2006;339:378–387. Available from: DOI: 10.1002/ardp.200600016
Mohamed Ahmed Elian Sophy and Mohamed Ahmed Mahmoud Abdel Reheim, Synthesis of Some New 1, 3, 4-Oxadiazole, Pyrazole, and Pyrimidine Bearing Thienopyrazole Moieties. 2020; 17(8):661- 670. Available from: DOI: 10.2174/1570179417999200730215318
Zeinab AM, Fatimah Alshehrei, Mohie EMZ, Thoraya A. Farghaly and Magda A. Abdallah. Synthesis of Novel Bis-pyrazole Derivatives as Antimicrobial Agents, Mini-Reviews in Medicinal Chemistry. 2019; 19(15):1276-1290. Available from: DOI: 10.2174/1389557519666190313095545
Alina Secrieru, Paul Michael O’Neill, Maria Lurdes, Santos Cristiano, Revisiting the Structure and Chemistry of 3(5)-Substituted Pyrazoles. Molecules. 2020; 25:42-44. Available from: doi:10.3390/molecules25010042
Wenquan Z, Honglei X, Rujing Y, Jiaheng Z, Kangcai W, Qinghua Z. Synthesis and Properties of 3,6-Dinitropyrazolo[4,3-c]- pyrazole (DNPP) Derivatives. Propellents. Explosives Pyrotechnics. 2020;45(4):546- 553. Available from: https://doi.org/10.1002/prep.201900205
Madhusudana P, Anuradha C. M. and Chitta S. K. Design, synthesis, and evaluation of pyrazolo-pyrazole derivatives on Methylisocitratelyase of Pseudomonas aeruginosa: in silico and in vitro study. Journal of Biomolecular Structure and Dynamics. 2017;35(11):2509-2529. Available from: DOI: 10.1080/07391102.2016.1223754
Sobhi M, Hassan G. M, Abdel-aziz A, El-Reedy A.M. Facile Synthesis of Pyrazolo[3,4-c]pyrazoles Bearing Coumarin Ring as Anticancer Agents. Journal of Heterocyclic Chemistry. 2018;55(8):1960-1965. Available from: https://doi.org/10.1002/jhet.3235
Silva VLM and Silva AMS. Recent Advances in the synthesis, functionalization and applications of Pyrazole-Type Compounds. Molecules. 2021;26(16):4989. Available from: https://doi.org/10.3390/molecules26164989
Mallikarjunna RR, Musthak AM and Sreeramulu J. Synthesis and antimicrobial activity of linked heterocycles containing pyrazolyle-indole derivatives. Journal of Pharmacy Research. 2012;5:1518-1521. Available from: DOI:10.1016/j.ejmech.2014.06.001
Steinbach G, Lynch PM, Robin KSP, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med. 2000;342:1946–1952. Available from: DOI: 10.1056/NEJM200006293422603
Mandawad GG, Dawane BS, Beedkar SD, Khobragade CN, Yemul OS. Trisubstituted thiophene analogues of 1-thiazolyl-2-pyrazoline, superoxidase inhibitors and free radical scavenger. Bioorg. Med. Chem. 2013;2:365-72. Available from: DOI: 10.1016/j.bmc.2012.09.060
Prakash O, Sharma D, Kamal R, Kumar R, Nair RR. The chemistry of α,β-ditosyloxyketones: new and convenient route for the synthesis of 1,4,5- trisubstituted pyrazoles from a,b-chalcone ditosylates. Tetrahedron. 2009;65:10175–10181. Available from: DOI:10.1016/j.tet.2009.10.001
Pisoschi AM, Cheregi MC and Danet, AF. Total antioxidant capacity of some commercial fruit juices: electrochemical and spectrophotometrical approaches. Molecules. 2009;14:480-493. Available from: https://doi.org/10.3390/molecules14010480
Winter CA, Fisley EA, Nuss GW. Carrageenin-induced edema in hind paws of the rat as an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med. 1964;111:544–547. Available from: DOI: 10.3181/00379727-111-27849
Published


How to Cite
Issue
Section
Copyright (c) 2024 Varun Kumar, Chennu MM Prasada Rao, Pragi Arora

This work is licensed under a Creative Commons Attribution 4.0 International License.