Towards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: Biological activities, molecular modeling and QSAR studies

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61988987%3A17110%2F16%3AA1801RWU" target="_blank" >RIV/61988987:17110/16:A1801RWU - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60162694:G44__/16:43875629 RIV/62690094:18450/16:50004827 RIV/61989100:27240/16:86097518 RIV/00179906:_____/16:10326636

Výsledek na webu

<a href="http://dx.doi.org/10.1016/j.ejmech.2016.05.058" target="_blank" >http://dx.doi.org/10.1016/j.ejmech.2016.05.058</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2016.05.058" target="_blank" >10.1016/j.ejmech.2016.05.058</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Towards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: Biological activities, molecular modeling and QSAR studies

Popis výsledku v původním jazyce

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 C-12 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. (C) 2016 Elsevier Masson SAS. All rights reserved.

Název v anglickém jazyce

Towards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: Biological activities, molecular modeling and QSAR studies

Popis výsledku anglicky

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 C-12 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. (C) 2016 Elsevier Masson SAS. All rights reserved.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

ISSN

0223-5234

e-ISSN

1768-3254

Svazek periodika

121

Číslo periodika v rámci svazku

10/2016

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

13

Strana od-do

699-711

Kód UT WoS článku

000382269700056

EID výsledku v databázi Scopus

2-s2.0-84975450946