This research was focused on in silico characterization and in vitro biological testing of the series of the compounds carrying a N-arylpiperazine moiety. The in silico investigation was based on the prediction of electronic, steric and lipohydrophilic features. The molecules were screened against Mycobacterium avium subsp. paratuberculosis CIT03, M. smegmatis ATCC 700084, M. kansasii DSM 44162, M. marinum CAMP 5644, Staphylococcus aureus ATCC 29213, methicillin-resistant S. aureus 63718, Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Candida albicans CCM 8261, C. parapsilosis CCM 8260 and C. krusei 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 M. kansasii was found for 1-[3-(3-ethoxyphenylcarbamoyl)oxy-2-hydroxypropyl]-4-(3-trifluoromethylphenyl)piperazin-1-ium chloride (MIC = 31.75 μM), which was comparable to the activity of isoniazid (INH; MIC = 29.17 μM). Moreover, 1-{2-hydroxy-3-(3-methoxyphenylcarbamoyl)oxy)propyl}-4-(4-fluorophenyl)piperazin-1-ium chloride was even more effective (MIC = 17.62 μM) against given mycobacterium. Among the tested N-arylpiperazines, 1-{2-hydroxy-3-(4-methoxyphenylcarbamoyl)oxy)propyl}-4-(3-trifluorometh-ylphenyl)piperazin-1-ium chloride was the most efficient against M. marinum (MIC = 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.

• Keywords
• Mycobacterium kansasii, Mycobacterium marinum, N-arylpiperazines, electronic properties, lipophilicity, structure–activity,
• Publication type
• Journal Article MeSH

The development of novel antimicrobial agents represents a timely research topic. Eighteen salicylanilide 4-(trifluoromethyl)benzoates were evaluated against Mycobacterium tuberculosis, M. avium and M. kansasii, eight bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA) and for the inhibition of mycobacterial isocitrate lyase. Some compounds were further screened against drug-resistant M. tuberculosis and for their cytotoxicity. Minimum inhibitory concentrations (MICs) for all mycobacterial strains were within 0.5-32 μmol/L, with 4-chloro-2-[4-(trifluoromethyl)phenylcarbamoyl]phenyl 4-(trifluoromethyl)benzoate superiority. Gram-positive bacteria including MRSA were inhibited with MICs ³ 0.49 μmol/L, while Gram-negative ones were much less susceptible. Salicylanilide 4-(trifluoromethyl)benzoates showed significant antibacterial properties, for many strains being comparable to standard drugs (isoniazid, benzylpenicillin) with no cross-resistance. All esters showed mild inhibition of mycobacterial isocitrate lyase and four compounds were comparable to 3-nitropropionic acid without a direct correlation between in vitro MICs and enzyme inhibition.

• MeSH
• Anti-Bacterial Agents pharmacology   MeSH
• Benzoates pharmacology   MeSH
• Nitro Compounds pharmacology   MeSH
• Isocitrate Lyase antagonists & inhibitors   metabolism   MeSH
• Methicillin-Resistant Staphylococcus aureus drug effects   MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium avium drug effects   MeSH
• Mycobacterium kansasii drug effects   MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Propionates pharmacology   MeSH
• Salicylanilides pharmacology   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 3-nitropropionic acid MeSH Browser
• Anti-Bacterial Agents MeSH
• Benzoates MeSH
• Nitro Compounds MeSH
• Isocitrate Lyase MeSH
• Propionates MeSH
• salicylanilide MeSH Browser
• Salicylanilides MeSH

The increasing emergence especially of drug-resistant tuberculosis has led to a strong demand for new anti-tuberculosis drugs. Eighteen salicylanilide benzoates were evaluated for their inhibition potential against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii; minimum inhibitory concentration values ranged from 0.5 to 16 μmol/L. The most active esters underwent additional biological assays. Four benzoates inhibited effectively the growth of five multidrug-resistant strains and one extensively drug-resistant strain of M. tuberculosis at low concentrations (0.25–2 μmol/L) regardless of the resistance patterns. The highest rate of multidrug-resistant mycobacteria inhibition expressed 4-chloro-2-[4-(trifluoromethyl)-phenylcarbamoyl]phenyl benzoate (0.25–1 μmol/L). Unfortunately, the most potent esters were still considerably cytotoxic, although mostly less than their parent salicylanilides.

• MeSH
• Antitubercular Agents pharmacology   toxicity   MeSH
• Benzoates pharmacology   toxicity   MeSH
• Hep G2 Cells MeSH
• Inhibitory Concentration 50 MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Drug Resistance, Multiple, Bacterial MeSH
• Mycobacterium avium drug effects   MeSH
• Mycobacterium kansasii drug effects   MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Salicylanilides pharmacology   toxicity   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antitubercular Agents MeSH
• Benzoates MeSH
• Salicylanilides MeSH