吡唑类化合物的合成及抗肿瘤活性分析
Synthesis and Antitumor Activity Analysis of Pyrazole Compounds
DOI: 10.12677/HJMCe.2022.102012, PDF,   
作者: 王玉琳, 周庆发*：中国药科大学理学院，江苏 南京
关键词: 吡唑；吡唑衍生物；抗肿瘤活性；Pyrazoles； Pyrazole Derivatives； Antitumor Activity
摘要: 吡唑是一类具有多种生理学活性的含氮五元杂环。在过去的十年里，越来越多的研究表明吡唑环类化合物可通过影响细胞分裂过程中关键酶，以及对特定肿瘤细胞系的抗增殖效应从而达到优秀的抗肿瘤效果。为进一步研究吡唑衍生物的抗肿瘤性质及其构效关系，以便充分开发这些化合物的抗肿瘤潜力，我们总结了合成吡唑及其衍生物的策略，并证明了这类化合物可以靶向发现新的抗肿瘤药物。
Abstract: Pyrazoles are a class of nitrogen-containing five-membered heterocycles with various physiological activities. In the past decade, more and more studies have shown that pyrazole compounds can achieve excellent antitumor effects by affecting key enzymes in the process of cell division and an-tiproliferative effects on specific tumor cell lines. To further study the antitumor properties of py-razole derivatives and their structure-activity relationships in order to fully exploit the antitumor potential of these compounds, we summarize strategies for the synthesis of pyrazoles and their de-rivatives, and demonstrate that such compounds can be targeted for discovery of new antitumor drugs.
文章引用：王玉琳, 周庆发. 吡唑类化合物的合成及抗肿瘤活性分析[J]. 药物化学, 2022, 10(2): 122-132. https://doi.org/10.12677/HJMCe.2022.102012

参考文献

[1] Abdellatif, K.R.A. and Fadaly, W.A. (2017) Design, Synthesis, Cyclooxygenase Inhibition and Biological Evaluation of New 1,3,5-Triaryl-4,5-Dihydro-1H-Pyrazole Derivatives Possessing Amino/Methanesulfonyl Pharmacophore. Bioor-ganic Chemistry, 70, 57-66. [Google Scholar] [CrossRef] [PubMed]
[2] Abdellatif, K.R.A., Abdelall, E.K.A., Lamie, P.F., Labib, M.B., El-Nahaas, E.S. and Abdelhakeem, M.M. (2020) New Pyrazole Derivatives Pos-sessing Amino/Methanesulphonyl Pharmacophore with Good Gastric Safety Profile: Design, Synthesis, Cyclooxygenase Inhibition, Anti-Inflammatory Activity and Histopathological Studies. Bioorganic Chemistry, 95, Article ID: 103540. [Google Scholar] [CrossRef] [PubMed]
[3] Abdel-Maksoud, M.S., El-Gamal, M.I., Gamal El-Din, M.M., Choi, Y., Choi, J., Shin, J.S., Kang, S.Y., Yoo, K.H., Lee, K.T., Baek, D. and Oh, C.H. (2018) Synthesis of New Tri-arylpyrazole Derivatives Possessing Terminal Sulfonamide Moiety and Their Inhibitory Effects on PGE2 and Nitric Ox-ide Productions in Lipopolysaccharide-Induced RAW 264.7 Macrophages. Molecules, 23, Article No. 2556. [Google Scholar] [CrossRef] [PubMed]
[4] El-Shoukrofy, M.S., Abd El Razik, H.A., AboulWafa, O.M., Bayad, A.E. and El-Ashmawy, I.M. (2019) Pyrazoles Containing Thiophene, Thienopyrimidine and Thienotriazolopy-rimidine as COX-2 Selective Inhibitors: Design, Synthesis, in Vivo Anti-Inflammatory Activity, Docking and in Silico Chemo-Informatic Studies. Bioorganic Chemistry, 85, 541-557. [Google Scholar] [CrossRef] [PubMed]
[5] Farooq, M., Sharma, A., Almarhoon, Z., Al-Dhfyan, A., El-Faham, A., Taha, N.A., Wadaan, M.A.M., Torre, B.G. and Albericio, F. (2019) Design and Synthesis of Mono-and Di-Pyrazolyl-s-Triazine Derivatives, Their Anticancer Profile in Human Cancer Cell Lines, and in Vivo Toxicity in Zebrafish Embryos. Bioorganic Chemistry, 87, 457-464. [Google Scholar] [CrossRef] [PubMed]
[6] Florentino, I.F., Silva, D.P.B., Cardoso, C.S., Menegatti, R., de Carvalho, F.S., Liao, L.M., Pinto, P.M., Peigneur, S., Costa, E.A. and Tytgat, J. (2019) Antinociceptive Effects of New Pyrazoles Compounds Mediated by the ASIC-1α Channel, TRPV-1 and μMOR Receptors. Biomedicine & Pharma-cotherapy, 115, Article ID: 108915. [Google Scholar] [CrossRef] [PubMed]
[7] Oliveira, D.H., Sousa, F.S.S., Birmann, P.T., Alves, D., Jacob, R.G., Savegnago, L. (2020) Antinociceptive and Anti-Inflammatory Effects of 4-(Arylchalcogenyl)-1H-Pyrazoles Con-taining Selenium or Sulfur. Pharmacological Reports, 72, 36-46. [Google Scholar] [CrossRef] [PubMed]
[8] Pratik, K., Arun, K., Neha, S., Bhumika, Y., Anshuman, S. and Kumar, G.S. (2018) Synthesis, Characterization of Ethyl 5-(Substituted)-1H-Pyrazole-3-Carboxylate Derivative as Potent Anti-inflammatory Agents. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 17, 32-38. [Google Scholar] [CrossRef] [PubMed]
[9] Taher, A.T., Mostafa Sarg, M.T., El-Sayed Ali, N.R. and Hilmy Elnagdi, N. (2019) Design, Synthesis, Modeling Studies and Biological Screening of Novel Pyrazole Deriva-tives as Potential Analgesic and Anti-Inflammatory Agents. Bioorganic Chemistry, 89, Article ID: 103023. [Google Scholar] [CrossRef] [PubMed]
[10] Yao, H., Guo, Q., Wang, M., Wang, R. and Xu, Z. (2021) Discovery of Pyrazole N-Aryl Sulfonate: A Novel and Highly Potent Cyclooxygenase-2 (COX-2) Selective Inhibitors. Bioorganic & Medicinal Chemistry, 46, Article ID: 116344. [Google Scholar] [CrossRef] [PubMed]
[11] Knorr, L. (1883) Einwirkung von acetessigester auf phenylhydra-zin. European Journal of Inorganic Chemistry, 16, 2597-2599. [Google Scholar] [CrossRef] 
[12] Girish, Y.R., Kumar, K.S.S., Manasa, H.S. and Shashikanth, S. (2014) ZnO: An Ecofriendly, Green Nano-Catalyst for the Synthesis of Pyrazole Derivatives under Aqueous Media. Journal of the Chinese Chemical Society, 61, 1175-1179. [Google Scholar] [CrossRef] 
[13] O’Shea, P., Gosselin, F., Webster, R., Reamer, R., Tillyer, R. and Grabowski, E. (2006) Highly Regioselective Synthesis of 1-Aryl-3,4,5-Substituted Pyrazoles. Synlett, 2006, 3267-3270. [Google Scholar] [CrossRef] 
[14] Bishop, B., Brands, K., Gibb, A. and Kennedy, D. (2003) Regioselec-tive Synthesis of 1,3,5-Substituted Pyrazoles from Acetylenic Ketones and Hydrazines. Synthesis, 2004, 43-52. [Google Scholar] [CrossRef] 
[15] Rao, V.K., Tiwari, R., Chhikara, B.S., Shirazi, A.N., Parang, K. and Kumar, A. (2013) Copper Triflate-Mediated Synthesis of 1,3,5-Triarylpyrazoles in [Bmim][PF6] Ionic Liquid and Evalu-ation of Their Anticancer Activities. RSC Advances, 3, 15396-15403. [Google Scholar] [CrossRef] [PubMed]
[16] Kat-ritzky, A.R., Wang, M., Zhang, S., Voronkov, M.V. and Steel, P.J. (2001) Regioselective Synthesis of Polysubstituted Pyrazoles and Isoxazoles. The Journal of Organic Chemistry, 66, 6787-6791. [Google Scholar] [CrossRef] [PubMed]
[17] He, S., Chen, L., Niu, Y.N., Wu, L.Y. and Liang, Y.M. (2009) 1,3-Dipolar Cycloaddition of Diazoacetate Compounds to Terminal Alkynes Promoted by Zn(OTf)2: An Efficient Way to the Preparation of Pyrazoles. Tetrahedron Letters, 50, 2443-2445. [Google Scholar] [CrossRef] 
[18] Gioiello, A., Khamidullina, A., Fulco, M.C., Venturoni, F., Zlot-sky, S. and Pellicciari, R. (2009) New One-Pot Synthesis of Pyrazole-5-Carboxylates by 1,3-Dipole Cycloadditions of Ethyl Diazoacetate with α-Methylene Carbonyl Compounds. Tetrahedron Letters, 50, 5978-5980. [Google Scholar] [CrossRef] 
[19] Delaunay, T., Genix, P., Es-Sayed, M., Vors, J.P., Monteiro, N. and Balme, G. (2010) A Modular Sydnone Cycloaddition/Suzuki-Miyaura Cross-Coupling Strategy to Unsymmetrical 3,5-Bis (Hetero) Aromatic Pyrazoles. Organic Letters, 12, 3328-3331. [Google Scholar] [CrossRef] [PubMed]
[20] Oh, L.M. (2006) Synthesis of Celecoxib via 1,3-Dipolar Cycloaddition. Tetrahedron Letters, 47, 7943-7946. [Google Scholar] [CrossRef] 
[21] Yadav, J.S., Reddy, B.V.S., Srinivas, M., Prabhakar, A. and Jagadeesh, B. (2004) Montmorillonite KSF Clay-Promoted Synthesis of Enantiomerically Pure 5-Substituted Pyrazoles from 2,3-Dihydro-4H-Pyran-4-Ones. Tetrahedron Letters, 45, 6033-6036. [Google Scholar] [CrossRef] 
[22] Xie, F., Cheng, G. and Hu, Y. (2006) Three-Component, One-Pot Reaction for the Combinatorial Synthesis of 1,3,4-Substituted Pyrazoles. Journal of Combinatorial Chemistry, 8, 286-288. [Google Scholar] [CrossRef] [PubMed]
[23] Ilhan, I.Ö., Saripinar, E. and Akçamur, Y. (2005) Synthesis of Some Pyrazole-3-Carboxylic Acid Hydrazide and Pyrazolopyridazine Compounds. Journal of Heterocyclic Chemistry, 42, 117-120. [Google Scholar] [CrossRef] 
[24] Krishnaiah, A. and Narsaiah, B. (2002) A Novel Ap-proach to the Synthesis of 5 Trifluoromethyl-3-Substituted Pyrazoles. Journal of Fluorine Chemistry, 115, 9-11. [Google Scholar] [CrossRef] 
[25] Liu, J.J., Zhang, H., Sun, J., Wang, Z.C., Yang, Y.S., Li, D.D., Zhang, F., Gong, H.B. and Zhu, H.L. (2012) Synthesis, Biological Evaluation of Novel 4,5-Dihydro-2H-Pyrazole 2-Hydroxyphenyl Derivatives as BRAF Inhibitors. Bioorganic & Medicinal Chemistry, 20, 6089-6096. [Google Scholar] [CrossRef] [PubMed]
[26] Sun, J., Lv, X.H., Qiu, H.Y., Wang, Y.T., Du, Q.R., Li, D.D., Yang, Y.H. and Zhu, H.L. (2013) Synthesis, Biological Evaluation and Molecular Docking Studies of Pyrazole Deriva-tives Coupling with a Thiourea Moiety as Novel CDKs Inhibitors. European Journal of Medicinal Chemistry, 68, 1-9. [Google Scholar] [CrossRef] [PubMed]
[27] Xu, Y., Liu, X.H., Saunders, M., Pearce, S., Foulks, J.M., Par-nell, K.M., Clifford, A., Nix, R.N., Bullough, J., Hendrickson, T.F., Wright, K., McCullar, M.V., Kanner, S.B. and Ho, K.K. (2014) Discovery of 3-(Trifluoromethyl)- 1H-Pyrazole-5-Carboxamide Activators of the M2 Isoform of Pyruvate Kinase (PKM2). Bioorganic & Medicinal Chemistry, 24, 515-519. [Google Scholar] [CrossRef] [PubMed]
[28] Li, X., Lu, X., Xing, M., Yang, X.H., Zhao, T.T., Gong, H.B. and Zhu, H.L. (2012) Synthesis, Biological Evaluation, and Molecular Docking Studies of N,1,3-Triphenyl-1H-Pyrazole-4-Carboxamide Derivatives as Anticancer Agents. Bioorganic & Medicinal Chemistry, 22, 3589-3593. [Google Scholar] [CrossRef] [PubMed]
[29] Huang, Y.Y., Wang, L.Y., Chang, C.H., Kuo, Y.H., Kaneko, K., Takayama, H., Kimura, M., Juang, S.H. and Wong, F.F. (2012) One-Pot Synthesis and Antiproliferative Evaluation of Pyrazolo[3,4-d]Pyrimidine Derivatives. Tetrahedron, 68, 9658-9664. [Google Scholar] [CrossRef] 
[30] Abdellatif, K.R.A. and Fadaly, W.A. (2017) Design, Synthesis, Cyclooxygenase Inhibition and Biological Evaluation of New 1,3,5-Triaryl-4,5-Dihydro-1H-Pyrazole Derivatives Possessing Amino/Methanesulfonyl Pharmacophore. Bioor-ganic Chemistry, 70, 57-66. [Google Scholar] [CrossRef] [PubMed]
[31] Abdellatif, K.R.A., Abdelall, E.K.A., Lamie, P.F., Labib, M.B., El-Nahaas, E.S. and Abdelhakeem, M.M. (2020) New Pyrazole Derivatives Pos-sessing Amino/Methanesulphonyl Pharmacophore with Good Gastric Safety Profile: Design, Synthesis, Cyclooxygenase Inhibition, Anti-Inflammatory Activity and Histopathological Studies. Bioorganic Chemistry, 95, Article ID: 103540. [Google Scholar] [CrossRef] [PubMed]
[32] Abdel-Maksoud, M.S., El-Gamal, M.I., Gamal El-Din, M.M., Choi, Y., Choi, J., Shin, J.S., Kang, S.Y., Yoo, K.H., Lee, K.T., Baek, D. and Oh, C.H. (2018) Synthesis of New Tri-arylpyrazole Derivatives Possessing Terminal Sulfonamide Moiety and Their Inhibitory Effects on PGE2 and Nitric Ox-ide Productions in Lipopolysaccharide-Induced RAW 264.7 Macrophages. Molecules, 23, Article No. 2556. [Google Scholar] [CrossRef] [PubMed]
[33] El-Shoukrofy, M.S., Abd El Razik, H.A., AboulWafa, O.M., Bayad, A.E. and El-Ashmawy, I.M. (2019) Pyrazoles Containing Thiophene, Thienopyrimidine and Thienotriazolopy-rimidine as COX-2 Selective Inhibitors: Design, Synthesis, in Vivo Anti-Inflammatory Activity, Docking and in Silico Chemo-Informatic Studies. Bioorganic Chemistry, 85, 541-557. [Google Scholar] [CrossRef] [PubMed]
[34] Farooq, M., Sharma, A., Almarhoon, Z., Al-Dhfyan, A., El-Faham, A., Taha, N.A., Wadaan, M.A.M., Torre, B.G. and Albericio, F. (2019) Design and Synthesis of Mono-and Di-Pyrazolyl-s-Triazine Derivatives, Their Anticancer Profile in Human Cancer Cell Lines, and in Vivo Toxicity in Zebrafish Embryos. Bioorganic Chemistry, 87, 457-464. [Google Scholar] [CrossRef] [PubMed]
[35] Florentino, I.F., Silva, D.P.B., Cardoso, C.S., Menegatti, R., de Carvalho, F.S., Liao, L.M., Pinto, P.M., Peigneur, S., Costa, E.A. and Tytgat, J. (2019) Antinociceptive Effects of New Pyrazoles Compounds Mediated by the ASIC-1α Channel, TRPV-1 and μMOR Receptors. Biomedicine & Pharma-cotherapy, 115, Article ID: 108915. [Google Scholar] [CrossRef] [PubMed]
[36] Oliveira, D.H., Sousa, F.S.S., Birmann, P.T., Alves, D., Jacob, R.G., Savegnago, L. (2020) Antinociceptive and Anti-Inflammatory Effects of 4-(Arylchalcogenyl)-1H-Pyrazoles Con-taining Selenium or Sulfur. Pharmacological Reports, 72, 36-46. [Google Scholar] [CrossRef] [PubMed]
[37] Pratik, K., Arun, K., Neha, S., Bhumika, Y., Anshuman, S. and Kumar, G.S. (2018) Synthesis, Characterization of Ethyl 5-(Substituted)-1H-Pyrazole-3-Carboxylate Derivative as Potent Anti-inflammatory Agents. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 17, 32-38. [Google Scholar] [CrossRef] [PubMed]
[38] Taher, A.T., Mostafa Sarg, M.T., El-Sayed Ali, N.R. and Hilmy Elnagdi, N. (2019) Design, Synthesis, Modeling Studies and Biological Screening of Novel Pyrazole Deriva-tives as Potential Analgesic and Anti-Inflammatory Agents. Bioorganic Chemistry, 89, Article ID: 103023. [Google Scholar] [CrossRef] [PubMed]
[39] Yao, H., Guo, Q., Wang, M., Wang, R. and Xu, Z. (2021) Discovery of Pyrazole N-Aryl Sulfonate: A Novel and Highly Potent Cyclooxygenase-2 (COX-2) Selective Inhibitors. Bioorganic & Medicinal Chemistry, 46, Article ID: 116344. [Google Scholar] [CrossRef] [PubMed]
[40] Knorr, L. (1883) Einwirkung von acetessigester auf phenylhydra-zin. European Journal of Inorganic Chemistry, 16, 2597-2599. [Google Scholar] [CrossRef] 
[41] Girish, Y.R., Kumar, K.S.S., Manasa, H.S. and Shashikanth, S. (2014) ZnO: An Ecofriendly, Green Nano-Catalyst for the Synthesis of Pyrazole Derivatives under Aqueous Media. Journal of the Chinese Chemical Society, 61, 1175-1179. [Google Scholar] [CrossRef] 
[42] O’Shea, P., Gosselin, F., Webster, R., Reamer, R., Tillyer, R. and Grabowski, E. (2006) Highly Regioselective Synthesis of 1-Aryl-3,4,5-Substituted Pyrazoles. Synlett, 2006, 3267-3270. [Google Scholar] [CrossRef] 
[43] Bishop, B., Brands, K., Gibb, A. and Kennedy, D. (2003) Regioselec-tive Synthesis of 1,3,5-Substituted Pyrazoles from Acetylenic Ketones and Hydrazines. Synthesis, 2004, 43-52. [Google Scholar] [CrossRef] 
[44] Rao, V.K., Tiwari, R., Chhikara, B.S., Shirazi, A.N., Parang, K. and Kumar, A. (2013) Copper Triflate-Mediated Synthesis of 1,3,5-Triarylpyrazoles in [Bmim][PF6] Ionic Liquid and Evalu-ation of Their Anticancer Activities. RSC Advances, 3, 15396-15403. [Google Scholar] [CrossRef] [PubMed]
[45] Kat-ritzky, A.R., Wang, M., Zhang, S., Voronkov, M.V. and Steel, P.J. (2001) Regioselective Synthesis of Polysubstituted Pyrazoles and Isoxazoles. The Journal of Organic Chemistry, 66, 6787-6791. [Google Scholar] [CrossRef] [PubMed]
[46] He, S., Chen, L., Niu, Y.N., Wu, L.Y. and Liang, Y.M. (2009) 1,3-Dipolar Cycloaddition of Diazoacetate Compounds to Terminal Alkynes Promoted by Zn(OTf)2: An Efficient Way to the Preparation of Pyrazoles. Tetrahedron Letters, 50, 2443-2445. [Google Scholar] [CrossRef] 
[47] Gioiello, A., Khamidullina, A., Fulco, M.C., Venturoni, F., Zlot-sky, S. and Pellicciari, R. (2009) New One-Pot Synthesis of Pyrazole-5-Carboxylates by 1,3-Dipole Cycloadditions of Ethyl Diazoacetate with α-Methylene Carbonyl Compounds. Tetrahedron Letters, 50, 5978-5980. [Google Scholar] [CrossRef] 
[48] Delaunay, T., Genix, P., Es-Sayed, M., Vors, J.P., Monteiro, N. and Balme, G. (2010) A Modular Sydnone Cycloaddition/Suzuki-Miyaura Cross-Coupling Strategy to Unsymmetrical 3,5-Bis (Hetero) Aromatic Pyrazoles. Organic Letters, 12, 3328-3331. [Google Scholar] [CrossRef] [PubMed]
[49] Oh, L.M. (2006) Synthesis of Celecoxib via 1,3-Dipolar Cycloaddition. Tetrahedron Letters, 47, 7943-7946. [Google Scholar] [CrossRef] 
[50] Yadav, J.S., Reddy, B.V.S., Srinivas, M., Prabhakar, A. and Jagadeesh, B. (2004) Montmorillonite KSF Clay-Promoted Synthesis of Enantiomerically Pure 5-Substituted Pyrazoles from 2,3-Dihydro-4H-Pyran-4-Ones. Tetrahedron Letters, 45, 6033-6036. [Google Scholar] [CrossRef] 
[51] Xie, F., Cheng, G. and Hu, Y. (2006) Three-Component, One-Pot Reaction for the Combinatorial Synthesis of 1,3,4-Substituted Pyrazoles. Journal of Combinatorial Chemistry, 8, 286-288. [Google Scholar] [CrossRef] [PubMed]
[52] Ilhan, I.Ö., Saripinar, E. and Akçamur, Y. (2005) Synthesis of Some Pyrazole-3-Carboxylic Acid Hydrazide and Pyrazolopyridazine Compounds. Journal of Heterocyclic Chemistry, 42, 117-120. [Google Scholar] [CrossRef] 
[53] Krishnaiah, A. and Narsaiah, B. (2002) A Novel Ap-proach to the Synthesis of 5 Trifluoromethyl-3-Substituted Pyrazoles. Journal of Fluorine Chemistry, 115, 9-11. [Google Scholar] [CrossRef] 
[54] Liu, J.J., Zhang, H., Sun, J., Wang, Z.C., Yang, Y.S., Li, D.D., Zhang, F., Gong, H.B. and Zhu, H.L. (2012) Synthesis, Biological Evaluation of Novel 4,5-Dihydro-2H-Pyrazole 2-Hydroxyphenyl Derivatives as BRAF Inhibitors. Bioorganic & Medicinal Chemistry, 20, 6089-6096. [Google Scholar] [CrossRef] [PubMed]
[55] Sun, J., Lv, X.H., Qiu, H.Y., Wang, Y.T., Du, Q.R., Li, D.D., Yang, Y.H. and Zhu, H.L. (2013) Synthesis, Biological Evaluation and Molecular Docking Studies of Pyrazole Deriva-tives Coupling with a Thiourea Moiety as Novel CDKs Inhibitors. European Journal of Medicinal Chemistry, 68, 1-9. [Google Scholar] [CrossRef] [PubMed]
[56] Xu, Y., Liu, X.H., Saunders, M., Pearce, S., Foulks, J.M., Par-nell, K.M., Clifford, A., Nix, R.N., Bullough, J., Hendrickson, T.F., Wright, K., McCullar, M.V., Kanner, S.B. and Ho, K.K. (2014) Discovery of 3-(Trifluoromethyl)- 1H-Pyrazole-5-Carboxamide Activators of the M2 Isoform of Pyruvate Kinase (PKM2). Bioorganic & Medicinal Chemistry, 24, 515-519. [Google Scholar] [CrossRef] [PubMed]
[57] Li, X., Lu, X., Xing, M., Yang, X.H., Zhao, T.T., Gong, H.B. and Zhu, H.L. (2012) Synthesis, Biological Evaluation, and Molecular Docking Studies of N,1,3-Triphenyl-1H-Pyrazole-4-Carboxamide Derivatives as Anticancer Agents. Bioorganic & Medicinal Chemistry, 22, 3589-3593. [Google Scholar] [CrossRef] [PubMed]
[58] Huang, Y.Y., Wang, L.Y., Chang, C.H., Kuo, Y.H., Kaneko, K., Takayama, H., Kimura, M., Juang, S.H. and Wong, F.F. (2012) One-Pot Synthesis and Antiproliferative Evaluation of Pyrazolo[3,4-d]Pyrimidine Derivatives. Tetrahedron, 68, 9658-9664. [Google Scholar] [CrossRef] 
[59] Abdellatif, K.R.A. and Fadaly, W.A. (2017) Design, Synthesis, Cyclooxygenase Inhibition and Biological Evaluation of New 1,3,5-Triaryl-4,5-Dihydro-1H-Pyrazole Derivatives Possessing Amino/Methanesulfonyl Pharmacophore. Bioor-ganic Chemistry, 70, 57-66. [Google Scholar] [CrossRef] [PubMed]
[60] Abdellatif, K.R.A., Abdelall, E.K.A., Lamie, P.F., Labib, M.B., El-Nahaas, E.S. and Abdelhakeem, M.M. (2020) New Pyrazole Derivatives Pos-sessing Amino/Methanesulphonyl Pharmacophore with Good Gastric Safety Profile: Design, Synthesis, Cyclooxygenase Inhibition, Anti-Inflammatory Activity and Histopathological Studies. Bioorganic Chemistry, 95, Article ID: 103540. [Google Scholar] [CrossRef] [PubMed]
[61] Abdel-Maksoud, M.S., El-Gamal, M.I., Gamal El-Din, M.M., Choi, Y., Choi, J., Shin, J.S., Kang, S.Y., Yoo, K.H., Lee, K.T., Baek, D. and Oh, C.H. (2018) Synthesis of New Tri-arylpyrazole Derivatives Possessing Terminal Sulfonamide Moiety and Their Inhibitory Effects on PGE2 and Nitric Ox-ide Productions in Lipopolysaccharide-Induced RAW 264.7 Macrophages. Molecules, 23, Article No. 2556. [Google Scholar] [CrossRef] [PubMed]
[62] El-Shoukrofy, M.S., Abd El Razik, H.A., AboulWafa, O.M., Bayad, A.E. and El-Ashmawy, I.M. (2019) Pyrazoles Containing Thiophene, Thienopyrimidine and Thienotriazolopy-rimidine as COX-2 Selective Inhibitors: Design, Synthesis, in Vivo Anti-Inflammatory Activity, Docking and in Silico Chemo-Informatic Studies. Bioorganic Chemistry, 85, 541-557. [Google Scholar] [CrossRef] [PubMed]
[63] Farooq, M., Sharma, A., Almarhoon, Z., Al-Dhfyan, A., El-Faham, A., Taha, N.A., Wadaan, M.A.M., Torre, B.G. and Albericio, F. (2019) Design and Synthesis of Mono-and Di-Pyrazolyl-s-Triazine Derivatives, Their Anticancer Profile in Human Cancer Cell Lines, and in Vivo Toxicity in Zebrafish Embryos. Bioorganic Chemistry, 87, 457-464. [Google Scholar] [CrossRef] [PubMed]
[64] Florentino, I.F., Silva, D.P.B., Cardoso, C.S., Menegatti, R., de Carvalho, F.S., Liao, L.M., Pinto, P.M., Peigneur, S., Costa, E.A. and Tytgat, J. (2019) Antinociceptive Effects of New Pyrazoles Compounds Mediated by the ASIC-1α Channel, TRPV-1 and μMOR Receptors. Biomedicine & Pharma-cotherapy, 115, Article ID: 108915. [Google Scholar] [CrossRef] [PubMed]
[65] Oliveira, D.H., Sousa, F.S.S., Birmann, P.T., Alves, D., Jacob, R.G., Savegnago, L. (2020) Antinociceptive and Anti-Inflammatory Effects of 4-(Arylchalcogenyl)-1H-Pyrazoles Con-taining Selenium or Sulfur. Pharmacological Reports, 72, 36-46. [Google Scholar] [CrossRef] [PubMed]
[66] Pratik, K., Arun, K., Neha, S., Bhumika, Y., Anshuman, S. and Kumar, G.S. (2018) Synthesis, Characterization of Ethyl 5-(Substituted)-1H-Pyrazole-3-Carboxylate Derivative as Potent Anti-inflammatory Agents. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 17, 32-38. [Google Scholar] [CrossRef] [PubMed]
[67] Taher, A.T., Mostafa Sarg, M.T., El-Sayed Ali, N.R. and Hilmy Elnagdi, N. (2019) Design, Synthesis, Modeling Studies and Biological Screening of Novel Pyrazole Deriva-tives as Potential Analgesic and Anti-Inflammatory Agents. Bioorganic Chemistry, 89, Article ID: 103023. [Google Scholar] [CrossRef] [PubMed]
[68] Yao, H., Guo, Q., Wang, M., Wang, R. and Xu, Z. (2021) Discovery of Pyrazole N-Aryl Sulfonate: A Novel and Highly Potent Cyclooxygenase-2 (COX-2) Selective Inhibitors. Bioorganic & Medicinal Chemistry, 46, Article ID: 116344. [Google Scholar] [CrossRef] [PubMed]
[69] Knorr, L. (1883) Einwirkung von acetessigester auf phenylhydra-zin. European Journal of Inorganic Chemistry, 16, 2597-2599. [Google Scholar] [CrossRef] 
[70] Girish, Y.R., Kumar, K.S.S., Manasa, H.S. and Shashikanth, S. (2014) ZnO: An Ecofriendly, Green Nano-Catalyst for the Synthesis of Pyrazole Derivatives under Aqueous Media. Journal of the Chinese Chemical Society, 61, 1175-1179. [Google Scholar] [CrossRef] 
[71] O’Shea, P., Gosselin, F., Webster, R., Reamer, R., Tillyer, R. and Grabowski, E. (2006) Highly Regioselective Synthesis of 1-Aryl-3,4,5-Substituted Pyrazoles. Synlett, 2006, 3267-3270. [Google Scholar] [CrossRef] 
[72] Bishop, B., Brands, K., Gibb, A. and Kennedy, D. (2003) Regioselec-tive Synthesis of 1,3,5-Substituted Pyrazoles from Acetylenic Ketones and Hydrazines. Synthesis, 2004, 43-52. [Google Scholar] [CrossRef] 
[73] Rao, V.K., Tiwari, R., Chhikara, B.S., Shirazi, A.N., Parang, K. and Kumar, A. (2013) Copper Triflate-Mediated Synthesis of 1,3,5-Triarylpyrazoles in [Bmim][PF6] Ionic Liquid and Evalu-ation of Their Anticancer Activities. RSC Advances, 3, 15396-15403. [Google Scholar] [CrossRef] [PubMed]
[74] Kat-ritzky, A.R., Wang, M., Zhang, S., Voronkov, M.V. and Steel, P.J. (2001) Regioselective Synthesis of Polysubstituted Pyrazoles and Isoxazoles. The Journal of Organic Chemistry, 66, 6787-6791. [Google Scholar] [CrossRef] [PubMed]
[75] He, S., Chen, L., Niu, Y.N., Wu, L.Y. and Liang, Y.M. (2009) 1,3-Dipolar Cycloaddition of Diazoacetate Compounds to Terminal Alkynes Promoted by Zn(OTf)2: An Efficient Way to the Preparation of Pyrazoles. Tetrahedron Letters, 50, 2443-2445. [Google Scholar] [CrossRef] 
[76] Gioiello, A., Khamidullina, A., Fulco, M.C., Venturoni, F., Zlot-sky, S. and Pellicciari, R. (2009) New One-Pot Synthesis of Pyrazole-5-Carboxylates by 1,3-Dipole Cycloadditions of Ethyl Diazoacetate with α-Methylene Carbonyl Compounds. Tetrahedron Letters, 50, 5978-5980. [Google Scholar] [CrossRef] 
[77] Delaunay, T., Genix, P., Es-Sayed, M., Vors, J.P., Monteiro, N. and Balme, G. (2010) A Modular Sydnone Cycloaddition/Suzuki-Miyaura Cross-Coupling Strategy to Unsymmetrical 3,5-Bis (Hetero) Aromatic Pyrazoles. Organic Letters, 12, 3328-3331. [Google Scholar] [CrossRef] [PubMed]
[78] Oh, L.M. (2006) Synthesis of Celecoxib via 1,3-Dipolar Cycloaddition. Tetrahedron Letters, 47, 7943-7946. [Google Scholar] [CrossRef] 
[79] Yadav, J.S., Reddy, B.V.S., Srinivas, M., Prabhakar, A. and Jagadeesh, B. (2004) Montmorillonite KSF Clay-Promoted Synthesis of Enantiomerically Pure 5-Substituted Pyrazoles from 2,3-Dihydro-4H-Pyran-4-Ones. Tetrahedron Letters, 45, 6033-6036. [Google Scholar] [CrossRef] 
[80] Xie, F., Cheng, G. and Hu, Y. (2006) Three-Component, One-Pot Reaction for the Combinatorial Synthesis of 1,3,4-Substituted Pyrazoles. Journal of Combinatorial Chemistry, 8, 286-288. [Google Scholar] [CrossRef] [PubMed]
[81] Ilhan, I.Ö., Saripinar, E. and Akçamur, Y. (2005) Synthesis of Some Pyrazole-3-Carboxylic Acid Hydrazide and Pyrazolopyridazine Compounds. Journal of Heterocyclic Chemistry, 42, 117-120. [Google Scholar] [CrossRef] 
[82] Krishnaiah, A. and Narsaiah, B. (2002) A Novel Ap-proach to the Synthesis of 5 Trifluoromethyl-3-Substituted Pyrazoles. Journal of Fluorine Chemistry, 115, 9-11. [Google Scholar] [CrossRef] 
[83] Liu, J.J., Zhang, H., Sun, J., Wang, Z.C., Yang, Y.S., Li, D.D., Zhang, F., Gong, H.B. and Zhu, H.L. (2012) Synthesis, Biological Evaluation of Novel 4,5-Dihydro-2H-Pyrazole 2-Hydroxyphenyl Derivatives as BRAF Inhibitors. Bioorganic & Medicinal Chemistry, 20, 6089-6096. [Google Scholar] [CrossRef] [PubMed]
[84] Sun, J., Lv, X.H., Qiu, H.Y., Wang, Y.T., Du, Q.R., Li, D.D., Yang, Y.H. and Zhu, H.L. (2013) Synthesis, Biological Evaluation and Molecular Docking Studies of Pyrazole Deriva-tives Coupling with a Thiourea Moiety as Novel CDKs Inhibitors. European Journal of Medicinal Chemistry, 68, 1-9. [Google Scholar] [CrossRef] [PubMed]
[85] Xu, Y., Liu, X.H., Saunders, M., Pearce, S., Foulks, J.M., Par-nell, K.M., Clifford, A., Nix, R.N., Bullough, J., Hendrickson, T.F., Wright, K., McCullar, M.V., Kanner, S.B. and Ho, K.K. (2014) Discovery of 3-(Trifluoromethyl)- 1H-Pyrazole-5-Carboxamide Activators of the M2 Isoform of Pyruvate Kinase (PKM2). Bioorganic & Medicinal Chemistry, 24, 515-519. [Google Scholar] [CrossRef] [PubMed]
[86] Li, X., Lu, X., Xing, M., Yang, X.H., Zhao, T.T., Gong, H.B. and Zhu, H.L. (2012) Synthesis, Biological Evaluation, and Molecular Docking Studies of N,1,3-Triphenyl-1H-Pyrazole-4-Carboxamide Derivatives as Anticancer Agents. Bioorganic & Medicinal Chemistry, 22, 3589-3593. [Google Scholar] [CrossRef] [PubMed]
[87] Huang, Y.Y., Wang, L.Y., Chang, C.H., Kuo, Y.H., Kaneko, K., Takayama, H., Kimura, M., Juang, S.H. and Wong, F.F. (2012) One-Pot Synthesis and Antiproliferative Evaluation of Pyrazolo[3,4-d]Pyrimidine Derivatives. Tetrahedron, 68, 9658-9664. [Google Scholar] [CrossRef]