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dc.contributor.authorDoležal, Rafael
dc.contributor.authorSoukup, Ondřej
dc.contributor.authorMaliňák, David
dc.contributor.authorSavedra, Ranylson M. L.
dc.contributor.authorMarek, Jan
dc.contributor.authorDolezalova, Marie
dc.contributor.authorPasdiorová, Markéta
dc.contributor.authorSalajková, Šárka
dc.contributor.authorKorábečný, Jan
dc.contributor.authorHonegr, Jan
dc.contributor.authorRamalho, Teodorico C.
dc.contributor.authorKuča, Kamil
dc.date.accessioned2016-09-30T12:18:02Z
dc.date.available2016-09-30T12:18:02Z
dc.date.issued2016
dc.identifier.citationEuropean Journal of Medicinal Chemistry. 2016, vol. 121, p. 699-711.cs
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.urihttp://hdl.handle.net/10084/112092
dc.description.abstractIn 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.cs
dc.language.isoencs
dc.publisherElseviercs
dc.relation.ispartofseriesEuropean Journal of Medicinal Chemistrycs
dc.relation.urihttp://dx.doi.org/10.1016/j.ejmech.2016.05.058cs
dc.rights© 2016 Elsevier Masson SAS. All rights reserved.cs
dc.subjectquaternary ammoniums saltscs
dc.subjectantimicrobialscs
dc.subjectsurfactantscs
dc.subjectmolecular modelingcs
dc.subjectmolecular dynamicscs
dc.subjectQSARcs
dc.titleTowards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: biological activities, molecular modeling and QSAR studiescs
dc.typearticlecs
dc.identifier.doi10.1016/j.ejmech.2016.05.058
dc.type.statusPeer-reviewedcs
dc.description.sourceWeb of Sciencecs
dc.description.volume121cs
dc.description.lastpage711cs
dc.description.firstpage699cs
dc.identifier.wos000382269700056


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