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Activity of N-Phenylpiperazine Derivatives Against Bacterial and Fungal Pathogens

[ Vol. 20 , Issue. 11 ]

Author(s):

Sarka Pospisilova, Pavlina Marvanova*, Jakub Treml, Agnes M. Moricz, Peter G. Ott, Petr Mokry, Klara Odehnalova, Ondrej Sedo, Alois Cizek and Josef Jampilek*   Pages 1119 - 1129 ( 11 )

Abstract:


Background: As the bacterial resistance to antibacterial chemotherapeutics is one of the greatest problems in modern medicine, efforts are made to develop new antimicrobial drugs. Compounds with a piperazine ring have proved to be promising agents against various pathogens.

Objective: The aim of the study was to prepare a series of new N-phenylpiperazines and determine their activity against various pathogens.

Method: Target compounds were prepared by multi-step synthesis starting from an appropriate substituted acid to an oxirane intermediate reacting with 1-(4-nitrophenyl)piperazine. Lipophilicity and pKa values were experimentally determined. Other molecular parameters were calculated. The inhibitory activity of the target compounds against Staphylococcus aureus, four mycobacteria strains, Bipolaris sorokiniana, and Fusarium avenaceum was tested. In vitro antiproliferative activity was determined on a THP-1 cell line, and toxicity against plant was determined using Nicotiana tabacum.

Results: In general, most compounds demonstrated only moderate effects. 1-(2-Hydroxy-3-{[4-(propan- 2-yloxy)benzoyl]oxy}propyl)-4-(4-nitrophenyl)piperazinediium dichloride and 1-{3-[(4-butoxybenzoyl)- oxy]-2-hydroxypropyl}-4-(4-nitrophenyl)piperazinediium dichloride showed the highest inhibition activity against M. kansasii (MIC = 15.4 and 15.0 µM, respectively) and the latter also against M. marinum (MIC = 15.0 µM). 1-(2-Hydroxy-3-{[4-(2-propoxyethoxy)benzoyl]oxy}propyl)-4-(4-nitrophenyl)piperazinediium dichloride had the highest activity against F. avenaceum (MIC = 14.2 µM). All the compounds showed only insignificant toxic effects on human and plant cells.

Conclusion: Ten new 1-(4-nitrophenyl)piperazine derivatives were prepared and analyzed, and their antistaphylococcal, antimycobacterial, and antifungal activities were determined. The activity against M. kansasii was positively influenced by higher lipophilicity, the electron-donor properties of substituent R and a lower dissociation constant. The exact mechanism of action will be investigated in follow-up studies.

Keywords:

N-phenylpiperazines, synthesis, lipophilicity, dissociation constant, antimycobacterials, antifungals, cytotoxicity.

Affiliation:

Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc, Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Department of Molecular Biology and Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Plant Protection Institute, Centre for Agricultural Research, Hungarian Academy of Sciences, Budapest, Plant Protection Institute, Centre for Agricultural Research, Hungarian Academy of Sciences, Budapest, Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Research Group of Proteomics, Central European Institute of Technology, Masaryk University, Brno, Department of Infectious Diseases and Microbiology, Faculty of Veterinary Medicine, University of Veterinary and Pharmaceutical Sciences, Brno, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Olomouc

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