Synthesis of N-acylalkylpyrazoles and the influence of their structure on cytotoxicity properties
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DOI:
https://doi.org/10.32523/2616-6771-2025-152-3-43-57Keywords:
pyrazole, N-acylalkylation, α-bromoketones, NMR, X-ray structural analysis, cytotoxicity, Artemia SalinaAbstract
Pyrazole and its derivatives are π-electron-excess aromatic heterocyclic compounds, the ring structure of which contains two bonded nitrogen atoms. Pyrazoles are attracting increasing attention of scientists due to their extensive and diverse range of biologically active properties. In this study a series of N-(acylalkyl)pyrazole derivatives were synthesized by reactions of aliphatic and aromatic α-bromideketones with pyrazole and its 3,5-dimethyl- and 3,5-diphenyl- derivatives via a two-stage one-pot reaction, in the presence of the K2CO3 base. Thus, new, previously undescribed N-pinacolopyrazoles with yields of 65–92% and N-phenacylpyrazoles with yields of 38–91% were obtained. The structures of the products were characterized by NMR, IR, X-ray diffraction and GC-mass spectrometry. According to the X-ray diffraction results, N-(acylalkyl)pyrazoles are conjugated π-systems, in the formation of crystals of which carbonyl groups participate. The cytotoxicity of the studied N-acylalkylpyrazoles towards Artemia Salina crustaceans has been determined, and the toxicity depends on the type of substituents. Thus, N-phenacylpyrazole has a cytotoxicity 6 times higher than the cytotoxicity of N-pinacolonpyrazole, and the cytotoxicity of N-phenacylpyrazoles varies depending on the substituents in the benzene ring, and decreases in the presence of acceptors. The results of the cytotoxicity study can be used to develop drugs with their further modification.
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References
Al-Aizari, F.A., Ansar, M.H., Karrouchi, K., Mabkhot, Y., Ramli, Y., Taoufik, J. (2018). Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review. Molecules 23, 1–86. https://doi.org/10.3390/molecules23010134
Alan, R.K. (1997). Comprehensive heterocyclic chemistry. Pyrazoles. In H. Richard (Eds.). John Wiley & Sons, Ltd, New York.
Ansari, A., Ali, A., Asif, M. (2017). Biologically active pyrazole derivatives: A Review. New Journal of Chemistry. 41. 16‒41. https://doi.org/10.1039/C6NJ03181A
Babaev, E.V., Panshina, S.Yu., Alzhapparova, N.A., Ibraev, M.K., Usenova, M.S. (2025). 3a,6a-Diazapentalenes (pyrazolo[1,2-a]pyrazoles). Russian Chemical Bulletin. 74, 1958–1975. https://doi.org/10.1007/s11172-025-4681-8
Baker, J. (1941). Mechanism and kinetics of aromatic side-chain substitution. Interpretation of reaction data by the method of relative energy levels. Transactions of the Faraday Society 37, 643. https://doi.org/10.1039/TF9413700632
Balasubrahmanya, K.S., Kiran, B.M., Ding-Yah, Y. (2023). 4-Chloro-3-nitrocoumarin as a precursor for synthesis of 2-arylchromeno[3,4-b]pyrrol-4(3H)-ones: a case of nitro group directed reductive coupling. Org. Biomol. Chem. 29, 5964–5969. https://doi.org/10.1039/d3ob00917c
Calenda, S., Catarzi, D., Varano, F., Vigiani, E., Volpini, R., Lambertucci, C., Spinaci, A., Trevisan, L., Grieco, I., Federico, S., Spalluto, G., Novello, G., Salmaso, V., Stefano, M.S., Colotta, V. (2024). Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta. Pharmaceuticals (Base l) 17, 468, 1‒31. https://doi.org/10.3390/ph17040468
Castillo, J.M., Portilla, J. (2019). Recent advances in the synthesis of new pyrazole derivatives. Italian Society of Chemistry, 194–223. https://doi.org/10.17374/targets.2019.22.194
Cour, T., Rasmussen, S.E., Hopf, H., Waisvisz, J.M., Hoeven, M.G., Carl-Gunnar, S. (1973). The structure of pyrazole, C3H4N2, at 295K and 108K as determined by X-Ray diffraction. Acta Chemica Scandinavica 27, 1845–1854. https://doi.org/10.3891/acta.chem.scand.27-1845
Dago, C.D., Maux, P.L., Roisnel, T., Brigaudeau, C., Bekro, Y.A., Mignen, O., Bazureau, J.P. (2018). Preliminary Structure-Activity Relationship (SAR) of a Novel Series of Pyrazole SKF-96365 Analogues as Potential Store-Operated Calcium Entry (SOCE) Inhibitors. Journal of Molecular Sciences 19, 2–24. https://doi.org/10.3390/ijms19030856
Dhiman, Sh., Nandwana, N.K., Saini, H.K., Kumar, D., Rangan, K., Robertson, K.N., Jhad, M., Kumara, A. (2018). Nickel-Catalyzed Tandem Knoevenagel Condensation and Intramolecular Direct Arylation: Synthesis of Pyrazolo[5,1-a]-isoquinoline Derivatives. Advanced Synthesis & Catalysis 360, 1973–1983. https://doi.org/10.1002/adsc.201701519
Elguero, J., Jagerovic, N. (1995). Solid state structure of NH-pyrazoles not easily amenable to crystal structure determinations: The case of 3(5)-phenyl-5(3)-methylpyrazole and 3,5-diphenyl-4-methylpyrazole. Journal of Heterocyclic Chemistry 32, 451–456. https://doi.org/10.1002/jhet.5570320211
Favilla, M., Macchia, L., Gallo, A., Altomare, C. (2006). Toxicity assessment of metabolites of fungal biocontrol agents using two different (Artemia salina and Daphnia magna) invertebrate bioassays. Food and Chemical Toxicology 44, 1922–1931. https://doi.org/10.1016/j.fct.2006.06.024
Karrouchi, K., Radi, S., Ramli, Y., Taoufik, J., Mabkhot, Y.N., Al-aizari, A.F., Ansar, M. (2018). Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review. Molecules 23, 1–86. https://doi.org/10.3390/molecules23010134
Katritzky, A.R., Wang, M., Zhang, S., Voronkov, M.V., Steel, P.J. (2001). Regioselective synthesis of polysubstituted pyrazoles and isoxazoles. The Journal of Organic Chemistry 66, 6787–6791. https://doi.org/10.1021/jo0101407
Kester, D.R., Duedall, I.W., Connors, D.N., Pytkowicz, R.M. (1967). Preparation of Artificial Seawater Archived. Limnology and Oceanography 12, 176–179. https://doi.org/10.4319/lo.1967.12.1.0176
Lei, J., Ding, Y., Tang, D.Y., Li, H., Xu, Z., Chen, Z. (2022). Efficient Synthesis of Pyrazoles by pH Dependent Isomerization of Enaminodiones. Asian Journal of Organic Chemistry 12, 1‒5. https://doi.org/10.1002/ajoc.202200448
Libralato, G., Prato, E., Migliore, L., Cicero, A.M., Manfra, L. (2016). A review of toxicity testing protocols and endpoints with Artemia spp. Ecological Indicators 69, 35–49. https://doi.org/10.1016/j.ecolind.2016.04.017
Martin, M.A.P., Fiss, G.F., Frizzo, C.P., Rosa, F.A., Bonacorso, H.G., Zanatta, N. (2010). Highly regioselective synthesis of novel 1,4'-bipyrazoles. Journal of the Brazilian Chemical Society 21, 240‒247. https://doi.org/10.1590/S0103-50532010000200008
Meyer, B.N., Ferrighi, N.R., Putnam, J.E., Jacobsen, L.B., Nichols, D.E., Laughlin, J.L. (1982). Brine shrimp: A convenient general bioassay for active plant constituents. Journal of Medicinal Plants Research 45, 31–34. https://doi.org/10.1055/s-2007-971236
Ozdemir, Z., Karakurt, A., Cali, U., Gunal, S., Isik, S., Sahin, Z.S., Dalkara S. (2015). Synthesis, anticonvulsant and antimicrobial activities of some new [1-(2-naphthyl)-2-(pyrazol-1-yl)ethanone]oxime ethers. Medicinal Chemistry 11, 41‒49. https://doi.org/10.2174/1573406410666140428150358
Perrin, D.D. (1965). Dissociation Constants of Organic Bases in Aqueous Solution, Supplement 1972, Butterworths, London. https://doi.org/10.1002/352760183X.ch5b
Rague Schleyer, P., Маеrкеr, C., Dransfeld, A., Jiao, H., Eikema Hommes, N.J.R. (1996). Nucleus-Independent Chemical Shifts: A Simple and Efficient Aromaticity Probe. J. Am. Chem. Soc. 118, 6317–6318. https://doi.org/10.1021/ja960582d
Salerno, L., Modica, M.N., Romeo, G., Pittalà V, Siracusa, M.A., Amato, M.E., Acquaviva, R., Di Giacomo, C., Sorrenti, V. (2012). Novel inhibitors of nitric oxide synthase with antioxidant properties. European Journal of Medicinal Chemistry 49, 118‒126. https://doi.org/10.1016/j.ejmech.2012.01.002
Schmidt, A., Dreger, A. (2011). Recent Advances in the Chemistry of Pyrazoles. Properties, Biological Activities, and Syntheses. Current Organic Chemistry 15, 1423–1463. https://doi.org/10.2174/138527211795378263
Secrieru, A., Michael, P.O., Cristiano, M.L.S. (2020). Revisiting the Structure and Chemistry of 3(5)-Substituted Pyrazoles. Molecules 25, 42. 1–28. https://doi.org/10.3390/molecules25010042
Sharma, T., Kumar, R., Chandra S., Sindhu, J., Singh, J., Singh, B., Mehta, S.K., Umar, A.S., Singh Saini, T., Kumar, V., Kataria, R. (2020). Synthesis, structural and pharmacological exploration of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-acetophenone oximes and their silver complexes. Polyhedron 195, 114972. https://doi.org/10.1016/j.poly.2020.114972
Sharma, T., Kumar, R., Sahoo, S.C., Sindhu, J., Singh, J., Singh, B., Mehta, S.K., Umar, A., Saini, T.S., Kumar, V., Kataria, R. (2021). Synthesis, structural and pharmacological exploration of 2-(3, 5-dimethyl-1H-pyrazol-1-yl)-acetophenone oximes and their silver complexes. Polyhedron 195, 114972. https://doi.org/10.1016/j.poly.2020.114972
Sikora, M., Katrusiak, A. (2013). Pressure-Controlled Neutral–Ionic Transition and Disordering of NH…N Hydrogen Bonds in Pyrazole. The Journal of Physical Chemistry C. 117, 10661–10668. https://doi.org/10.1021/jp401389v
Solis, P.N., Wright, C.W., Anderson, M.M., Gupta, M.P., Philhipson, J.D. (1993). A microwell Cytotoxicity Assay using Artemia salina (Brine Shrimp). Planta Med. 59, 250–252. https://doi.org/10.1055/s-2006-959661
Solomons, T.W., Calderazzo, J., Fowler, F.W. (1965). The Diazapentalene System. 1-Benzoyl-2-phenylpyrazolo[1,2-a]pyrazole Derivatives. Journal of the American Chemical Society 87, 528–531. https://doi.org/10.1021/ja01081a023
Stanovnik, B., Svete, J. (2003) Product Class 1: Pyrazoles. ChemInform 34, 215–225. https://doi.org/10.1002/chin.200346258
Suleimenov, E.M. (2009). Components of Peusedanum morisonii and their antimicrobial and cytotoxic activity. Chemistry of Natural Compounds 45, 710–711. https://doi.org/10.1007/s10600-009-9423-x
Unnava, R., Deka, M.J., Saikia, A.K. (2016). Synthesis of Highly Substituted 4-Iodopyrazole N-oxides and Pyrazoles from Propargylamines. Asian Journal of Organic Chemistry 5, 528–536. https://doi.org/10.1002/ajoc.201600002
Zhang, Y., Wu, C., Zhang, N., Fan, R., Ye, Y., Xu, J. (2023). Recent Advances in the Development of Pyrazole Derivatives as Anticancer Agents. International Journal of Molecular Sciences 24, 12724. https://doi.org/10.3390/ijms241612724
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Copyright (c) 2025 N. Alzhapparova, S. Panshina, M. Ibrayev, A. Zhumina, A. Orazbai (Author)
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