Synthesis and in vitro antimycobacterial activity of novel n-arylpiperazines containing an ethane-1,2-diyl connecting chain

Authors

Tomás Gonec, Veterinární a farmaceutická univerzita Brno
Ivan Malík, Comenius University
Jozef Csöllei, Veterinární a farmaceutická univerzita Brno
Josef Jampílek, Comenius University
Jirina Stolaríková, Zdravotního ústavu se sídlem v Ostrave
Ivan Solovic, National Institute for Tuberculosis Lung Diseases and Thoracic Surgery
Peter Miku, Comenius University
Stanislava Keltoová, Veterinární a farmaceutická univerzita Brno
Peter Kollár, Veterinární a farmaceutická univerzita Brno
Jim O'Mahony, Department of Biological Sciences, Cork Institute of Technology, Cork, IrelandFollow
Aidan Coffey, Department of Biological Sciences, Cork Institute of Technology, Cork, IrelandFollow

Document Type

Article

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Disciplines

Biology

Publication Details

Molecules

Abstract

© 2017 by the authors. Novel 1-(2-{3-/4-[(alkoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)-piperazin-1-ium chlorides (alkoxy = methoxy to butoxy; 8a-h) 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 (jM), varied from 2.113 (compound 8e) to 2.930 (8h) and indicated relatively high lipophilicity of these salts. Electronic properties of the molecules 8a-h were investigated by evaluation of their UV/Vis spectra. In a next phase of the research, the compounds 8a-h 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 8a-h 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 8a-h series are also discussed.

Recommended Citation

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.