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Molecules 2017, 22(12), 2100; doi:10.3390/molecules22122100

Synthesis and In Vitro Antimycobacterial Activity of Novel N-Arylpiperazines Containing an Ethane-1,2-diyl Connecting Chain

1
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences in Brno, Palackého 1946/1, Brno CZ-612 42, Czech Republic
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, Bratislava SK-832 32, Slovak Republic
3
Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health, Partyzánské náměstí 7, Ostrava CZ-702 00, Czech Republic
4
Clinic for Tuberculosis and Lung Diseases, National Institute for Tuberculosis, Lung Diseases and Thoracic Surgery, Vyšné Hágy, Vysoké Tatry SK-059 84, Slovak Republic
5
Department of Public Health, Faculty of Health, Catholic University in Ružomberok, Hrabovská cesta 1A, Ružomberok SK-034 01, Slovak Republic
6
Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, Bratislava SK-832 32, Slovak Republic
7
Department of Human Pharmacology and Toxicology, University of Veterinary and Pharmaceutical Sciences in Brno, Palackého 1946/1, Brno CZ-612 42, Czech Republic
8
Department of Biological Sciences, Cork Institute of Technology, Bishopstown, Cork T12 P928, Ireland
*
Author to whom correspondence should be addressed.
Received: 30 October 2017 / Revised: 20 November 2017 / Accepted: 27 November 2017 / Published: 30 November 2017
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Abstract

Novel 1-(2-{3-/4-[(alkoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)-piperazin-1-ium chlorides (alkoxy = methoxy to butoxy; 8ah) have been designed and synthesized through multistep reactions as a part of on-going research programme focused on finding new antimycobacterials. Lipophilic properties of these compounds were estimated by RP-HPLC using methanol/water mobile phases with a various volume fraction of the organic modifier. The log kw values, which were extrapolated from intercepts of a linear relationship between the logarithm of a retention factor k (log k) and volume fraction of a mobile phase modifier (ϕM), varied from 2.113 (compound 8e) to 2.930 (8h) and indicated relatively high lipophilicity of these salts. Electronic properties of the molecules 8ah were investigated by evaluation of their UV/Vis spectra. In a next phase of the research, the compounds 8ah were in vitro screened against M. tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794), M. kansasii CNCTC My 235/80 (identical with ATCC 12478), a M. kansasii 6 509/96 clinical isolate, M. avium CNCTC My 330/80 (identical with ATCC 25291) and M. avium intracellulare ATCC 13950, respectively, as well as against M. kansasii CIT11/06, M. avium subsp. paratuberculosis CIT03 and M. avium hominissuis CIT10/08 clinical isolates using isoniazid, ethambutol, ofloxacin, ciprofloxacin or pyrazinamide as reference drugs. The tested compounds 8ah were found to be the most promising against M. tuberculosis; a MIC = 8 μM was observed for the most effective 1-(2-{4-[(butoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)piperazin-1-ium chloride (8h). In addition, all of them showed low (insignificant) in vitro toxicity against a human monocytic leukemia THP-1 cell line, as observed LD50 values > 30 μM indicated. The structure–antimycobacterial activity relationships of the analyzed 8ah series are also discussed. View Full-Text
Keywords: N-arylpiperazines; arylaminoethanols; lipophilicity; electronic properties; Mycobacterium tuberculosis H37Rv N-arylpiperazines; arylaminoethanols; lipophilicity; electronic properties; Mycobacterium tuberculosis H37Rv
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MDPI and ACS Style

Goněc, T.; Malík, I.; Csöllei, J.; Jampílek, J.; Stolaříková, J.; Solovič, I.; Mikuš, P.; Keltošová, S.; Kollár, 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, 2100.

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