QSAR analysis employing Kubinyi's bilinear model was applied to examine the relationship between the structure (characterized by the lengths of the terminal hydrocarbon chain, m, and of the hydrocarbon spacer chain, y), lipophilicity (characterized by the chromatographic parameter Rm and aggregation properties expressed through the critical micellar concentration cK), and antimicrobial activity (characterized by the minimum inhibition concentration, MIC) of quaternary ammonium bolaamphiphiles. The log cK = f(m) dependence was found to be linear whereas the log (1/MIC) = f(m), log (1/MIC) = f(y), log (1/MIC) = f (log cK) and log (1/MIC) = f(Rm) dependences were nonlinear. The effect of the hydrophobic terminal chains (m) and of the hydrophobic spacer chain (y) on the aggregation properties and on the biological activity of the substances was studied.
New surface-active bisquaternary ammonium salts derived from bis-(2-dimethylaminoethyl) ester of glutaric acid are highly effective against representatives of Gram-positive, Gram-negative bacteria and yeasts. Relationships between structure, lipophilicity and antimicrobial effectiveness were demonstrated by quantitative structure-activity methodology. The non-linear dependence of biological activity on the structure as well as lipophilicity (expressed as critical micelle concentration-CMC) was shown using Kubinyi's bilinear model. The most effective compounds were those with the alkyl chain of 11-12 carbon atoms and with the CMC values around 0.7-1.0 mmol/L. These derivatives possessed higher antimicrobial activity particularly to Gram-negative bacteria.
The antimicrobials (1-methyldodecyl)dimethylamine oxide and (1-methyldodecyl)trimethylammonium bromide affect the cytoplasmic membrane of E. coli. The interaction results in release of intracellular material (K+, 260nm-absorbing material), an effect on dehydrogenase enzyme activity and inhibition of respiration. The final effect of both substances is the same; they differ only in their dynamics. The effect of the membrane was correlated with parameters characterizing these surfactants i.e. critical micelle concentration (c.m.c.) minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) over the concentration range of 10(-4) to 10(-1) mmol/dm3 of active substance. The three stage mode of action model can be summarized as follows: 1-polar (coulombic) interactions, 2-polar and hydrophobic interactions, 3-hydrophobic interactions (extraction and solubilization). The polar and hydrophobic interactions (1st and 2nd stage) are discussed also in relation to model membranes.
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