Antimicrobial activity of a series of 1-alkyl-2-(4-pyridyl)pyridinium bromides against Gram-Positive and Gram-Negative bacteria.

OBJECTIVE: To test a series of 1-alkyl-2-(4-pyridyl)pyridinium bromides with alkyl chains containing between 9 and 16 carbons against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli, Stenotrophomonas maltophilia, Acinetobacter baumannii and Pseudomonas aeruginosa) bacteria. MATERIALS AND METHODS: Chemical synthesis was based on the reaction of 2,4'-bipyridyl with alkyl bromide. Antimicrobial activity of the bipyridyls was measured by growing bacterial cultures on Mueller-Hinton agar in the presence and absence of inhibitors. RESULTS: The compounds were most active against S. aureus. The most active compounds had alkyl chain lengths of between 11 and 16 carbons. Methicillin-sensitive S. aureus was more susceptible to the inhibitors than methicillin-resistant S. aureus (MRSA). Two subclasses of MRSA existed which differed in their susceptibility to the inhibitors. The susceptibility of MRSA strains to the compounds was increased in the presence of the efflux pump inhibitor reserpine. The activity of the compounds against Gram-negative organisms was increased when the membrane-permeabilizing agent sodium citrate was introduced. Critical micelle concentrations of the compounds were much higher than minimum inhibitory concentrations of the inhibitors. CONCLUSION: The mechanism of action of the compounds may involve perturbing bacterial membranes. The resistance of some MRSA strains to the compounds may be related to efflux pumps.

Physico-chemical properties and spectrophotometric determination of biologically active 1-alkyl-2-(2-pyridyl)pyridinium bromides.

Physico-chemical properties of compounds prepared from 2,2'-bipyridine, 1-alkyl-2-(2-pyridyl)pyridinium bromides, were investigated by DC polarography and by GC-MS. Their ionization potentials were calculated. Additionally, the formation of associates with bromothymol blue and methyl orange during the spectrophotometric determination was measured. It was determined that 1-alkyl-2-(2-pyridyl)pyridinium ions are reduced by 2 one-electron steps in a DC polarography system. The reduction potentials are not related to the ionization potential values calculated for the substances investigated. The carcinogenic potential (tg alpha) of the parent compound 2,2'-bipyridine and of a series of 1-alkyl derivatives was very low indicating that the compounds are not carcinogenic. The MS fragmentation patterns indicate the low stability of the 1-alkyl substituents. It was shown that 2,2'-bipyridine is either fragmented to two pyridine ions or the--N=CH--fragments are removed. Additionally, spectrophotometric determinations of colored associates of 1-alkyl-2-(2-pyridyl)pyridinium bromides with bromothymol blue and methyl orange were investigated and the optimal condiditions for these determinations are reported.

QSAR and CAMM study of amphiphilic antimicrobially active 2,2'-bipyridyl monoammonium salts.

Preparation of 2,2'-bipyridyl monoammonium salts is described as well as their conformation study using computer aided molecular modelling (CAMM) methods and quantitative relations between structure, aggregation properties and antimicrobial activity (QSAR) of these derivatives. It was found that using the applied synthetic route the monoammonium salt is prepared free of bis-ammonium salt. While in the case of the unsubstituted 2,2'-bipyridyl the energy difference between s-cis and s-trans conformers is minor and the transition from one state into the other one is possible with s-trans state apparently being preferred, after quaternisation the exclusive conformer is s-cis that is in this state fixed except of steric hindrance between the alkyl substituent bonded to the N+ atom and the hydrogen bonded to 3'C also by a weak hydrogen interaction C-H ... N between the hydrogen of the first carbon of the alkyl chain and the nitrogen of the adjacent ring. This finding is supported also by the results of calculation of point electric charges, dipole moments, 2C-2'C distance and torsion angles of non-quaternised as well as bipyridinium cations. It follows from quantitative dependencies between lipophilicity (expressed by means of aggregation properties-by critical concentration of micelle formation ck, and chromatographic factor RM), structure (length of alkyl chain m) and antimicrobial activity (minimum inhibition concentration, MIC) that the maximum of activity is achieved with compounds of chain length m = 13 to 16 with ck about 1.10(-3) mol/l. It follows from the comparison with simple alkylpyridinium salts that the mechanism of biological activity at the bacterial level will not differ in 2,2'-dipyridyl derivatives from the mechanism of activity of other ammonium salts.