The synthesis and the antimicrobial activity of N1-substituted 5-amino-4-arylsulfonyl-3-N-phenylaminopyrazoles


  • P. V. Tkachenko National University of Pharmacy, Ukraine
  • O. V. Tkachenko National University of Pharmacy, Ukraine
  • K. Yu. Netosova National University of Pharmacy, Ukraine
  • O. V. Borisov Enamine Ltd, Ukraine
  • I. O. Zhuravel Kharkiv Medical Academy of Post-graduate Education, Ukraine
  • V. V. Kazmirchuk Mechnikov Institute of Microbiology and Immunology, Ukraine



5-aminopyrazole, synthesis, antimicrobial activity, antifungal activity


This article is continuation of the development of methods for the synthesis of small molecules based on the structure of 5-aminopyrazole. The synthesis and the antimicrobial activity for a series of new N1-subsituted 5-amino-4-arylsulfonyl-3-N-phenylaminopyrazoles have been described.
Aim. To synthesize derivatives of 5-amino-4-arylsulfonyl-3phenylaminopyrazoles and study their antimicrobial and antifungal properties.
Materials and methods. The methods of organic synthesis, instrumental methods of organic compounds analysis and methods of microbiological screening were used.
Results and discussion. 5-Amino-4-arylsulfonyl-3-phenylaminopyrazoles were prepared by the reaction of arylsulfonylacetonitriles with isothiocyanates in the presence of NaOH and CH3I with further cyclization with hydrazine hydrate. The reaction of this compounds with N-arylchloroacetamides finished a series of N1-substituted 5-amino-4-arylsulfonyl-3-phenylaminopyrazoles. The antibacterial and antifungal properties of the compounds synthesized were studied. Some of the compounds obtained appeared to be potent inhibitors for several pathogenic bacterial and fungal lines.
Conclusions. The synthetic scheme for obtaining of N1-substituted 5-amino-4-arylsulfonyl-3-phenylaminopyrazoles, which can be used for creation of a library of compounds for in vitro antimicrobial screening, has been proposed. Some of the compounds synthesized are of certain interest as potential pharmaceutical agents and can be used to develop new antifungal agents.

Author Biographies

P. V. Tkachenko, National University of Pharmacy

postgraduate student of the Drug and Analytical Toxicology Department

O. V. Tkachenko, National University of Pharmacy

Candidate of Pharmacy (Ph.D.), associate professor of the Quality Management Department

K. Yu. Netosova, National University of Pharmacy

Candidate of Pharmacy (Ph.D.), assistant professor of the Drug and Analytical Toxicology Department

O. V. Borisov, Enamine Ltd

Candidate of Chemistry (Ph.D.), head of the laboratory

I. O. Zhuravel, Kharkiv Medical Academy of Post-graduate Education

Doctor of Chemistry (Dr. habil.), professor, head of the Department of Clinical Biochemistry, Forensic Toxicology and Pharmacy

V. V. Kazmirchuk, Mechnikov Institute of Microbiology and Immunology

Candidate of Medicine (Ph.D.), head of the Antibacterial Agents Laboratory


Hughes, D. L. (2017). Patent Review of Manufacturing Routes to Fifth–Generation Cephalosporin Drugs. Part 1, Ceftolozane. Organic

Process Research & Development, 21 (3), 430–443. doi: 10.1021/acs.oprd.7b00033

Lawrence, H. R., Martin, M. P., Luo, Y., Pireddu, R., Yang, H., Gevariya, H., Ozcan, S., Zhu, J.–Y., Kendig, R., Rodriguez, M., Elias,

R., Cheng, J. Q., Sebti, S. M., Schonbrunn, E., Lawrence, N. J. (2012). Development of o–Chlorophenyl Substituted Pyrimidines as

Exceptionally Potent Aurora Kinase Inhibitors. Journal of Medicinal Chemistry, 55 (17), 7392–7416. doi: 10.1021/jm300334d

Bekhit, A. A., Ashour, H. M., Abdel Ghany, Y. S., Bekhit, Ael–D., Baraka, A. (2008). Synthesis and biological evaluation of some thiazolyl

and thiadiazolyl derivatives of 1H–pyrazole as anti–inflammatory antimicrobial agents. European Journal of Medicinal Chemistry,

(3), 456–463. doi: 10.1016/j.ejmech.2007.03.030

Weston, C. E., Krämer, A., Colin, F., Yildiz, Ö., Baud, M. G. J., Meyer–Almes, F., Fuchter, M. J. (2017). Toward Photopharmacological

Antimicrobial Chemotherapy Using Photoswitchable Amidohydrolase Inhibitors. ACS Infectious Diseases, 3(2), 152–161.

doi: 10.1021/acsinfecdis.6b00148

Tkachenko, P. V., Tkachenko, E. V., Zhuravel, I. A., Kazmirchuk, V. V., Derbisbekova, U. B. (2017). Vestnik KazNMU, 2, 307–311.

Tkachenko, P. V., Tkachenko, O. V., Netosova, K. Y., Borisov, O. V., Zhuravel, I. O. (2017). The synthesis of the substituted 4–alkyl/

arylsulfonyl–5–amino–3–alkylthiopyrazoles as promising pharmaceutical agents with the antifungal action. Vìsnik Farmacìï, 2(90),

–30. doi: 10.24959/nphj.17.2158

Bruno, O., Brullo, C., Bondavalli, F., Schenone, S., Ranise, A., Arduino, N., Bertolotto, M. B., Montecucco, F., Ottonello, L., Dallegri,

F., Tognolini, M., Ballabeni, V., Bertoni, S., Barocelli, E. (2007). Synthesis and Biological Evaluation of N–Pyrazolyl–N‘–alkyl/benzyl/

phenylureas: a New Class of Potent Inhibitors of Interleukin 8–Induced Neutrophil Chemotaxis. Journal of Medicinal Chemistry,

(15), 3618–3626. doi: 10.1021/jm0704402

Celoni, M., Godoya, M., Fighera, M. R., Souza, F. R., Flores, A. E., Rubin, M. A., Oliveira, M. R., Zanatta, N., Martins, M. A., Bonacorso,

H. G., Mello, C. F. (2004). α2–Adrenoceptors and 5–HT receptors mediate the antinociceptive effect of new pyrazolines, but not

of dipyrone. European Journal of Pharmacology, 496 (1–3), 93–97. doi: 10.1016/j.ejphar.2004.05.045

Smurnyy, Y., Toms, A. V., Hickson, G. R., Eck, M. J., Eggert, U. S. (2010). Binucleine 2, an isoform–specific inhibitor of Drosophila Aurora

B kinase, provides insights into the mechanism of cytokinesis. ACS Chemical Biology, 5 (11), 1015–1020. doi: 10.1021/cb1001685

Vizirianakis, I. S., Chatzopoulou, M., Bonovolias, I. D., Nicolaou, I., Demopoulos, V. J., Tsiftsoglou, A. S. (2010). Toward the Development

of Innovative Bifunctional Agents To Induce Differentiation and To Promote Apoptosis in Leukemia: Clinical Candidates and

Perspectives. Journal of Medicinal Chemistry, 53 (19), 6779–6810. doi: 10.1021/jm100189a

Swain, N., Batchelor, D., Beaudoin, S., Bechle, B., Bradley, P. (2017). Discovery of Clinical Candidate 4–[2–(5–Amino–1H–pyrazol–

–yl)–4–chlorophenoxy]–5–chloro–2–fluoro–N–1,3–thiazol–4–ylbenzenesulfonamide (PF–05089771): Design and Optimization

of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7. Journal of Medical Chemistry, 60 (16), 7029–7042. doi: 10.1021/


Planken, S., Behenna, D., Nair, S., Johnson, T., Nagata, A. (2017). Discovery of N–((3R,4R)–4–Fluoro–1–(6–((3–methoxy–1–methyl–

H–pyrazol–4–yl)amino)–9–methyl–9H–purin–2–yl)pyrrolidine–3–yl)acrylamide (PF–06747775) through Structure–Based Drug Design:

A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild–Type EGFR. Journal of

Medical Chemistry, 60 (7), 3002–3019. doi: 10.1021/acs.jmedchem.6b01894

Crawford, T. D., Romero, F. A., Lai, K.W., Tsui, V., Taylor, A. M. (2016). Discovery of a Potent and Selective in Vivo Probe (GNE–272)

for the Bromodomains of CBP/EP300. Journal of Medical Chemistry, 59 (23), 10549–10563. doi: 10.1021/acs.jmedchem.6b01022

Zhang, Ch.–H., Chen, K., Jiao, Y., Li, L., Li, Ya., Zhang, R., Zheng, M., Zhong, L., Huang, Sh., Song, Ch., Lin, W., Yang, J., Xiang,

R., Peng, B., Han, J., Lu, G., Wei, Y., Yang, Sh. (2016). From Lead to Drug Candidate: Optimization of 3–(Phenylethynyl)–1H–

pyrazolo[3,4–d]pyrimidin–4–amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer. Journal of Medical

Chemistry, 59 (21), 9788–9805. doi: 10.1021/acs.jmedchem.6b00943

Ai, T., Willett, R., Williams, J., Ding, R., Wilson, D. J., Xie, J., Kim, D. H., Puertollano, R., Chen, L. (2017). N–(1–Benzyl–3,5–dimethyl–

H–pyrazol–4–yl)benzamides: Antiproliferative Activity and Effects on mTORC1 and Autophagy. ACS Medicinal Chemistry

Letters, 8 (1), 90–95. doi: 10.1021/acsmedchemlett.6b00392

Kaufmann, K., Romaine, I., Days, E., Pascual, C., Malik, A., Yang, L., Zou, B., Du, Y., Sliwoski, G., Morrison, R. D., Denton, J., Niswender,

C. M., Daniels, J. S., Sulikowski, G. A., Xie, X. S., Lindsley, C. W., Weaver, C. D. (2013). ML297 (VU0456810), the first potent and

selective activator of the GIRK potassium channel, displays antiepileptic properties in mice. ACS Chemical Neuroscience, 4 (19),

–1286. doi: 10.1021/cn400062a

Wen, W., Wu, W., Romaine, I. M., Kaufmann, K., Du, Y., Sulikowski, G. A., Weaver, C. D., Lindsley, C. W. (2013). Discovery of

‘molecular switches’ within a GIRK activator scaffold that afford selective GIRK inhibitors. ACS Chemical Neuroscience, 23 (16),

–4566. doi: 10.1016/j.bmcl.2013.06.023

Wieting, J. M., Vadukoot, A. K., Sharma, S., Abney, K. K., Bridges, T. M., Daniels, J. S., Morrison, R. D., Wickman, K., Weaver,

C. D., Hopkins, C. R. (2017). Discovery and Characterization of 1H–Pyrazol–5–yl–2–phenylacetamides as Novel, Non–Urea–Containing

GIRK1/2 Potassium Channel Activators. ACS Chemical Neuroscience. doi: 10.1021/acschemneuro.7b00217

Dömling, A. (2006). Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry. Chemical Reviews,

(1), 17–89. doi: 10.1021/cr0505728

Shao, N., Chen, T., Zhang, T., Zhu, H., Zheng, Q., Zou, H. (2014). Cascade regioselective synthesis of pyrazoles from nitroallylic acetates

and N–tosyl hydrazine. Tetrahedron, 70 (4), 795–799. doi: 10.1016/j.tet.2013.12.046






Synthesis and Analysis of Biologically Active Substances