The Structure–Antimicrobial Activity Relationships of a Promising Class of the Compounds Containing the N-Arylpiperazine Scaffold

Abstract

This research was focused on <i>in silico</i> characterization and <i>in vitro</i> biological testing of the series of the compounds carrying a <i>N</i>-arylpiperazine moiety. The <i>in silico</i> investigation was based on the prediction of electronic, steric and lipohydrophilic features. The molecules were screened against <i>Mycobacterium avium</i> subsp. <i>paratuberculosis</i> CIT03, <i>M. smegmatis</i> ATCC 700084, <i>M. kansasii</i> DSM 44162, <i>M. marinum</i> CAMP 5644, <i>Staphylococcus aureus</i> ATCC 29213, methicillin-resistant <i>S. aureus</i> 63718, <i>Escherichia coli</i> ATCC 25922, <i>Enterococcus faecalis</i> ATCC 29212, <i>Candida albicans</i> CCM 8261, <i>C. parapsilosis</i> CCM 8260 and <i>C. krusei</i> CCM 8271, respectively, by standardized microdilution methods. The eventual antiproliferative (cytotoxic) impact of those compounds was examined on a human monocytic leukemia THP-1 cell line, as a part of the biological study. Promising potential against <i>M. kansasii</i> was found for 1-[3-(3-ethoxyphenylcarbamoyl)oxy-2-hydroxypropyl]-4-(3-trifluoromethylphenyl)piperazin-1-ium chloride (<i>MIC</i> = 31.75 μM), which was comparable to the activity of isoniazid (INH; <i>MIC</i> = 29.17 μM). Moreover, 1-{2-hydroxy-3-(3-methoxyphenylcarbamoyl)oxy)propyl}-4-(4-fluorophenyl)piperazin-1-ium chloride was even more effective (<i>MIC</i> = 17.62 μM) against given <i>mycobacterium</i>. Among the tested <i>N</i>-arylpiperazines, 1-{2-hydroxy-3-(4-methoxyphenylcarbamoyl)oxy)propyl}-4-(3-trifluorometh-ylphenyl)piperazin-1-ium chloride was the most efficient against <i>M. marinum</i> (<i>MIC</i> = 65.32 μM). One of the common features of all investigated substances was their insignificant antiproliferative (i.e., non-cytotoxic) effect. The study discussed structure-antimicrobial activity relationships considering electronic, steric and lipophilic properties.