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.
Graphical Abstract
[1]
European Centre for Disease Prevention and Control. Surveillance of antimicrobial resistance in Europe – Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) 2017; Stockholm ECDC, 2018.
[2]
Placinta, C.M.; D’Mello, J.P.F.; MacDonald, A.M.C. A review of worldwide contamination of cereal grains and animal feed with Fusarium mycotoxins. Anim. Feed Sci. Technol., 1999, 78(1-2), 21-37.
[3]
Lemke, T.L.; Williams, D.A. Foye’s Principles of Medicinal Chemistry, 7th ed; Lippincott Williams & Wilkins and Wolters Kluwer: Baltimore, MD, USA, 2013.
[4]
Welsch, M.; Snyder, S.; Stockwell, B. Privileged scaffolds for library design and drug discovery. Curr. Opin. Chem. Biol., 2010, 14(3), 347-361.
[5]
Horton, D.A.; Bourne, G.T.; Smythe, M.L. The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem. Rev., 2003, 103(3), 893-930.
[6]
Brickner, S.J.; Hutchinson, D.K.; Barbachyn, M.R.; Manninen, P.R.; Ulanowicz, D.A.; Garmon, S.A.; Grega, K.C.; Hendges, S.K.; Toops, D.S.; Ford, C.W.; Zurenko, G.E. Synthesis and antibacterial activity of U-100592 and U-100766, Two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections. J. Med. Chem., 1996, 39(3), 673-679.
[7]
Das, B.; Rudra, S.; Yadav, A.; Ray, A.; Raja Rao, A.V.S.; Srinivas, A.S.S.V.; Soni, A.; Saini, S.; Shukla, S.; Pandya, M.; Bhateja, P.; Malhotra, S.; Mathur, T.; Arora, S.K.; Rattan, A.; Mehta, A. Synthesis and SAR of novel oxazolidinones: Discovery of ranbezolid. Bioorg. Med. Chem. Lett., 2005, 15(19), 4261-4267.
[8]
Mahamoud, A.; Chevalier, J.; Alibert-Franco, S.; Kern, W.V.; Pages, J.M. Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy. J. Antimicrob. Chemother., 2007, 59(6), 1223-1229.
[9]
Foley, T.L.; Rai, G.; Yasgar, A.; Daniel, T.; Baker, H.L.; Attene-Ramos, M.; Kosa, N.M.; Leister, W.; Burkart, M.D.; Jadhav, A.; Simeonov, A.; Maloney, D.J. 4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267), a potent inhibitor of bacterial phosphopantetheinyl transferase that attenuates secondary metabolism and thwarts bacterial growth. J. Med. Chem., 2014, 57(3), 1063-1078.
[10]
Phoenix, D.A.; Harris, F.; Dennison, S.R. Novel Antimicrobial Agents and Strategies; Wiley-VCH: Weinheim, Germany, 2015.
[11]
Upadhayaya, R.S.; Vandavasi, J.K.; Kardile, R.A.; Lahore, S.V.; Dixit, S.S.; Deokar, H.S.; Shinde, P.D.; Sarman, M.P.; Chattopadhyaya, J. Novel quinoline and naphthalene derivatives as potent antimycobacterial agents. Eur. J. Med. Chem., 2010, 45(5), 1854-1867.
[12]
Malik, I.; Csollei, J.; Jampilek, J.; Stanzel, L.; Zadrazilova, I.; Hosek, J.; Pospisilova, S.; Cizek, A.; Coffey, A.; O’Mahony, J. The structure–antimicrobial activity relationships of promising class of the compounds containing N-arylpiperazine scaffold. Molecules, 2016, 21(10), 1274.
[13]
Gonec, T.; Malik, I.; Csollei, J.; Jampilek, J.; Stolarikova, J.; Solovic, I.; Mikus, P.; Keltosova, S.; Kollar, P.; O’Mahony, J.; Coffey, A. Synthesis and in vitro antimycobacterial activity of novel N-arylpiperazines containing an ethane-1,2-diyl connecting chain. Molecules, 2017, 22(12), 2100.
[14]
Bak, A.; Kozik, V.; Malik, I.; Jampilek, J.; Smolinski, A. Probability-driven 3D pharmacophore mapping of antimycobacterial potential of hybrid molecules combining phenylcarbamoyloxy and N-arylpiperazine fragments. SAR QSAR Environ. Res., 2018, 29(10), 801-821.
[15]
He, C.; Preiss, L.; Wang, B.; Fu, L.; Wen, H.; Zhang, X.; Cui, H.; Meier, T.; Yin, D. Structural simplification of bedaquiline: The discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline-derived antitubercular lead compounds. ChemMedChem, 2017, 12(2), 106-119.
[16]
Lowes, D.; Guiguemde, W.; Connelly, M.; Zhu, F.; Sigal, M.; Clark, J.; Lemoff, A.; Derisi, J.; Wilson, E.; Guy, A.R. Optimization of propafenone analogues as antimalarial leads. J. Med. Chem., 2011, 54(21), 7477-7485.
[17]
Schwinn, F.J. Ergosterol biosynthesis inhibitors. An overview of their history and contribution to medicine and agriculture. Pest Manag. Sci., 1984, 15(1), 40-47.
[18]
Sherald, J.L.; Sisler, H.D. Antifungal mode of action of triforine. Pestic. Biochem. Physiol., 1975, 5(5), 477-488.
[19]
Brent, K.J.; Hollomon, D.W. Fungicide resistance in crop pathogens: how can it be managed?, 2nd ed; Fungicide Resistance Action Committee: Brussels, 2007.
[20]
Wieczorek, D.; Lipok, J.; Borys, K.M.; Adamczyk‐Wozniak, A.; Sporzynski, A. Investigation of fungicidal activity of 3‐piperazine‐bis(benzoxaborole) and its boronic acid analogue. Appl. Organomet. Chem., 2014, 28(5), 347-350.
[21]
Francois, I.E.; Thevissen, K.; Pellens, K.; Meert, E.M.; Heeres, J.; Freyne, E.; Coesemans, E.; Viellevoye, M.; Deroose, F.; Martinez Gonzalez, S.; Pastor, J.; Corens, D.; Meerpoel, L.; Borgers, M.; Ausma, J.; Dispersyn, G.D.; Cammue, B.P. Design and synthesis of a series of piperazine‐1‐carboxamidine derivatives with antifungal activity resulting from accumulation of endogenous reactive oxygen species. ChemMedChem, 2009, 4(10), 1714-1721.
[22]
Bink, A.; Govaert, G. François, I.E.; Pellens, K.; Meerpoel, L.; Borgers, M.; Van Minnebruggen, G.; Vroome, V.; Cammue, B.P.; Thevissen, K. A fungicidal piperazine-1-carboxamidine induces mitochondrial fission-dependent apoptosis in yeast. FEMS Yeast Res., 2010, 10(7), 812-818.
[23]
Marvanova, P.; Padrtova, T.; Odehnalova, K.; Hosik, O.; Oravec, M.; Mokry, P. Synthesis and determination of physicochemical properties of new 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-alkoxyethoxy-benzoates. Molecules, 2016, 21(12), 1682.
[24]
Marvanova, P.; Padrtova, T.; Pekarek, T.; Brus, J.; Czernek, J.; Mokry, P.; Humpa, O.; Oravec, M.; Jampilek, J. Synthesis and characterization of new 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-propoxybenzoates and their hydrochloride salts. Molecules, 2016, 21(12), 707.
[25]
Vettorazzi, M.; Angelina, E.; Lima, S.; Gonec, T.; Otevrel, J.; Marvanova, P.; Padrtova, T.; Mokry, P.; Bobal, P.; Acosta, L.M.; Palma, A.; Cobo, J.; Bobalova, J.; Csollei, J.; Malik, I.; Alvarez, S.; Spiegel, S.; Jampilek, J.; Enriz, R. An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors. Eur. J. Med. Chem., 2017, 139, 461-481.
[26]
Gu, Z.; Wen, J.; Tang, W.; Wang, W.; Deng, B.; Wu, W.; Qu, T. Glucopyranosyl derivative and application thereof in medicines. Patent CN105461762 A. April 06, 2016.
[27]
Inukai, T.; Sato, H. P'-cyanophenylester der p-(betaalkoxy)
aethoxybenzoesaeure. Patent D2751403 A1. June 01, 1978.
[28]
Tengler, J.; Kapustikova, I.; Stropnicky, O.; Mokry, P.; Oravec, M. Csollei; J.; Jampilek, J. Synthesis of new (arylcarbonyloxy)aminopropanol derivatives and the determination of their physico-chemical properties. Cent. Eur. J. Chem., 2013, 11(11), 1757-1767.
[29]
Zadrazilova, I.; Pospisilova, S.; Masarikova, M.; Imramovsky, A.; Monreal-Ferriz, J.; Vinsova, J.; Cizek, A.; Jampilek, J. Salicylanilide carbamates: Promising antibacterial agents with high in vitro activity against methicillin-resistant Staphylococcus aureus. Eur. J. Pharm. Sci., 2015, 77, 197-207.
[30]
Imramovsky, A.; Pesko, M.; Kralova, K.; Vejsova, M.; Stolarikova, J.; Vinsova, J.; Jampilek, J. Investigating spectrum of biological activity of 4- and 5-chloro-2-hydroxy-n-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides. Molecules, 2011, 16(3), 2414-2430.
[31]
Pauk, K.; Zadrazilova, I.; Imramovsky, A.; Vinsova, J.; Pokorna, M.; Masarikova, M.; Cizek, A.; Jampilek, J. New derivatives of salicylamides: Preparation and antimicrobial activity against various bacterial species. Bioorg. Med. Chem., 2013, 21(21), 6574-6581.
[32]
Gonec, T.; Zadrazilova, I.; Nevin, E.; Kauerova, T.; Pesko, M.; Kos, J.; Oravec, M.; Kollar, P.; Coffey, A.; O’Mahony, J.; Cizek, A.; Kralova, K.; Jampilek, J. Synthesis and biological evaluation of N-alkoxyphenyl-3-hydroxynaphthalene-2-carboxanilides. Molecules, 2015, 20(6), 9767-9787.
[33]
Gonec, T.; Pospisilova, S.; Kauerova, T.; Kos, J.; Dohanosova, J.; Oravec, M.; Kollar, P.; Coffey, A.; Liptaj, T.; Cizek, A.; Jampilek, J. NAlkoxyphenylhydroxynaphthalenecarboxamides and their antimycobacterial activity. Molecules, 2016, 21(8), 1068.
[34]
Imramovsky, A.; Pesko, M.; Monreal-Ferriz, J.; Kralova, K.; Vinsova, J.; Jampilek, J. Photosynthesis-inhibiting efficiency of 4-chloro-2-(chlorophenyl-carbamoyl)phenyl alkyl-carbamates. Bioorg. Med. Chem. Lett., 2011, 21(15), 4564-4567.
[35]
Gonec, T.; Kralova, K.; Pesko, M.; Jampilek, J. Antimycobacterial N-Alkoxyphenylhydroxy-naphthalenecarboxamides affecting photosystem II. Bioorg. Med. Chem. Lett., 2017, 27(9), 1881-1885.
[36]
Tengler, J.; Kapustikova, I.; Pesko, M.; Govender, R.; Keltosova, S.; Mokry, P.; Kollar, P.; O’Mahony, J.; Coffey, A.; Kralova, K.; Jampilek, J. Synthesis and biological evaluation of 2-hydroxy-3-[(2-aryloxyethyl)amino]propyl 4-[(alkoxycarbonyl)-amino]benzoates. Scientific World J., 2013, 2013274570
[37]
Bueno, J. Antitubercular in vitro drug discovery: Tools for begin the search.In: Understanding Tuberculosis-New Approaches to Fighting against Drug Resistance; Cardona, P.J., Ed.; InTech: Rijeka, 2012, pp. 147-168.
[38]
Hamid, R.; Rotshteyn, Y.; Rabadi, L.; Parikh, R.; Bullock, P. Comparison of alamar blue and MTT assays for high through-put screening. Toxicol. In Vitro, 2004, 18(5), 703-710.
[39]
Martin, A.; Morcillo, N.; Lemus, D.; Montoro, E.; Telles, M.A.; Simboli, N.; Pontino, M.; Porras, T.; Leon, C.; Velasco, M.; Chacon, L.; Barrera, L.; Ritacco, V.; Portaels, F.; Palomino, J.C. Multicenter study of MTT and resazurin assays for testing susceptibility to first-line anti-tuberculosis drugs. Int. J. Tuberc. Lung Dis., 2005, 9(8), 901-906.
[40]
Wang, J.; McIntosh, F.; Radomski, N.; Dewar, K.; Simeone, R.; Enninga, J.; Brosch, R.; Rocha, E.P.; Veyrier, F.J.; Behr, M.A. Insights on the emergence of Mycobacterium tuberculosis from the analysis of Mycobacterium kansasii. Genome Biol. Evol., 2015, 7(3), 856-870.
[41]
Thoen, C.O.; Karlson, A.G.; Ellefson, R.D. Differentiation between Mycobacterium kansasii and Mycobacterium marinum by gas-liquid chromatographic analysis of cellular fatty acids. Appl. Microbiol., 1972, 24(6), 1009-1010.
[42]
Griffith, D.E. Management of disease due to Mycobacterium kansasii. Clin. Chest Med., 2002, 23(3), 613-621.
[43]
Suffness, M.; Douros, J. Current status of the NCI plant and animal product program. J. Nat. Prod., 1982, 45(1), 1-14.
[44]
Kauerova, T.; Kos, J.; Gonec, T.; Jampilek, J.; Kollar, P. Antiproliferative and pro-apoptotic effect of novel nitro-substituted hydroxynaphthanilides on human cancer cell lines. Int. J. Mol. Sci., 2016, 17(8), 1219.
[45]
Zadrazilova, I.; Pospisilova, S.; Pauk, K.; Imramovsky, A.; Vinsova, J.; Cizek, A.; Jampilek, J. In vitro bactericidal activity of 4- and 5-chloro-2-hydroxy-N-[1-oxo-1-(phenylamino)alkan-2-yl]-benzamides against MRSA. BioMed Res. Int., 2015, 2015349534
[46]
Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. The 8th Informational
Supplement Document; CLSI: Wayne, PA, USA, 2012, M100-S22.,
[47]
Abate, G.; Mshana, R.N.; Miorner, H. Evaluation of colorimetric assay based on 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) for rapid detection of rifampicin resistance in Mycobacterium tuberculosis. Int. J. Tuberc. Lung Dis., 1998, 2(12), 1011-1016.
[48]
Pospisilova, S.; Kos, J.; Michnova, H.; Kapustikova, I.; Strharsky, T.; Oravec, M.; Moricz, A.M.; Bakonyi, J.; Kauerova, T.; Kollar, P.; Cizek, A.; Jampilek, J. Synthesis and spectrum of biological activities of novel N-arylcinnamamides. Int. J. Mol. Sci., 2018, 19(8), 2318.
[49]
Hosek, J.; Bartos, M.; Chudik, S.; Dall’Acqua, S.; Innocenti, G.; Kartal, M.; Kokoska, L.; Kollar, P.; Kutil, Z.; Landa, P.; Marek, R.; Zavalova, V.; Zemlicka, M.; Smejkal, K. Natural compound cudraflavone B shows promising anti-inflammatory properties in vitro. J. Nat. Prod., 2011, 74(4), 614-619.
Related Journals
Protein & Peptide Letters
Related Books
Frontiers in Protein and Peptide Sciences
Article Metrics
21
2
1