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.

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

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

Biomedical Research Centre University Hospital Hradec Kralove Sokolska 581 500 05 Hradec Kralove Czech Republic; Department of Epidemiology Faculty of Military Health Sciences University of Defence Trebesska 1575 500 01 Hradec Kralove Czech Republic

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

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

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

Institute of Applied Informatics Faculty of Science University of South Bohemia Branisovska 1760 370 05 Ceske Budejovice Czech Republic

Laboratory of Molecular Modeling Chemistry Department Federal University of Lavras Lavras MG Brazil

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