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Towards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: Biological activities, molecular modeling and QSAR studies
R. Dolezal, O. Soukup, D. Malinak, RM. Savedra, J. Marek, M. Dolezalova, M. Pasdiorova, S. Salajkova, J. Korabecny, J. Honegr, TC. Ramalho, K. Kuca,
Jazyk angličtina Země Francie
Typ dokumentu časopisecké články
Grantová podpora
NV15-31847A
MZ0
CEP - Centrální evidence projektů
- MeSH
- antibakteriální látky chemie farmakologie toxicita MeSH
- Bacteria účinky léků MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- houby účinky léků MeSH
- hydrofobní a hydrofilní interakce MeSH
- křečci praví MeSH
- kvantitativní vztahy mezi strukturou a aktivitou * MeSH
- molekulární konformace MeSH
- pyridiny chemie farmakologie toxicita MeSH
- simulace molekulární dynamiky * MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.
Citace poskytuje Crossref.org
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- $a Dolezal, Rafael $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Rokitanskeho 62, 500 03, Czech Republic.
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- $a Towards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: Biological activities, molecular modeling and QSAR studies / $c R. Dolezal, O. Soukup, D. Malinak, RM. Savedra, J. Marek, M. Dolezalova, M. Pasdiorova, S. Salajkova, J. Korabecny, J. Honegr, TC. Ramalho, K. Kuca,
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- $a In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.
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- $a Soukup, Ondrej $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
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- $a Malinak, David $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Physiology and Pathophysiology, Faculty of Medicine, University of Ostrava, Syllabova 19, 703 00, Ostrava, Czech Republic.
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- $a Savedra, Ranylson M L $u Laboratory of Molecular Modeling, Chemistry Department, Federal University of Lavras, Lavras, MG, Brazil.
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- $a Dolezalova, Marie $u Institute of Applied Informatics, Faculty of Science, University of South Bohemia, Branisovska 1760, 370 05, Ceske Budejovice, Czech Republic.
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- $a Korabecny, Jan $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
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- $a Honegr, Jan $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Cybernetics and Biomedical Engineering, Faculty of Electrical Engineering and Computer Science, VSB-Technical University of Ostrava, 17. Listopadu 15, 708 33, Ostrava-Poruba, Czech Republic.
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- $a Ramalho, Teodorico C $u Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Rokitanskeho 62, 500 03, Czech Republic; Laboratory of Molecular Modeling, Chemistry Department, Federal University of Lavras, Lavras, MG, Brazil.
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- $a Kuca, Kamil $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Rokitanskeho 62, 500 03, Czech Republic. Electronic address: kamil.kuca@fnhk.cz.
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