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

ABSTRACT: 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 ?M), which was comparable to the activity of isoniazid (INH; MIC = 29.17 ?M). Moreover, 1-{2-hydroxy-3-(3-methoxyphenylcarbamoyl)oxy)propyl}-4-(4-fluorophenyl)piperazin-1-ium chloride was even more effective (MIC = 17.62 ?M) 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 ?M). 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.

SUBMITTER: Malik I

PROVIDER: S-EPMC6273431 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Malík Ivan I Csöllei Jozef J Jampílek Josef J Stanzel Lukáš L Zadražilová Iveta I Hošek Jan J Pospíšilová Šárka Š Čížek Alois A Coffey Aidan A O'Mahony Jim J

Molecules (Basel, Switzerland) 20160926 10

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, Staphylococcu ...[more]

PMID: 27681720

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Project description:Mitochondria play a central role in metabolic homeostasis, and dysfunction of this organelle underpins the etiology of many heritable and aging-related diseases. Tetrapeptides with alternating cationic and aromatic residues such as SS-31 (elamipretide) show promise as therapeutic compounds for mitochondrial disorders. In this study, we conducted a quantitative structure-activity analysis of three alternative tetrapeptide analogs, benchmarked against SS-31, that differ with respect to aromatic side chain composition and sequence register. We present the first structural models for this class of compounds, obtained with Nuclear Magnetic Resonance (NMR) and molecular dynamics approaches, showing that all analogs except for SS-31 form compact reverse turn conformations in the membrane-bound state. All peptide analogs bound cardiolipin-containing membranes, yet they had significant differences in equilibrium binding behavior and membrane interactions. Notably, analogs had markedly different effects on membrane surface charge, supporting a mechanism in which modulation of membrane electrostatics is a key feature of their mechanism of action. The peptides had no strict requirement for side chain composition or sequence register to permeate cells and target mitochondria in mammalian cell culture assays. All four peptides were pharmacologically active in serum withdrawal cell stress models yet showed significant differences in their abilities to restore mitochondrial membrane potential, preserve ATP content, and promote cell survival. Within our peptide set, the analog containing tryptophan side chains, SPN10, had the strongest impact on most membrane properties and showed greatest efficacy in cell culture studies. Taken together, these results show that side chain composition and register influence the activity of these mitochondria-targeted peptides, helping provide a framework for the rational design of next-generation therapeutics with enhanced potency.

Dataset Information

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

Publications

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

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