Synthesis and Properties of Cleavable Quaternary Ammonium Compounds.

Quaternary ammonium compounds are widely used as antiseptic and disinfectant. It is been a concern that their widespread use will lead to an increase of environmental problems, therefore the development of biodegradable surfactants is necessary. The present research is aimed at the design of novel amphiphilic molecules with similar properties to those already known but more biodegradable. Based on benzalkonium chloride (BAC), novel carbonate cleavable surfactants (CBAC) were synthesized. The breakable carbonate sites make CBAC compounds more degradable and potentially more biodegradable than their non-cleavable BAC analogues. Natural products such as fatty alcohols (C8-C16) and N,N-dimethyl-2-aminoethanol were used as reagents for the synthesis of CBAC8-16. These amphiphilic compounds were characterized in terms of surface properties and antimicrobial activity against Gram-positive and Gram-negative bacteria, yeasts and moulds. The novel surfactants showed similar surface activities in aqueous solutions when compared to BAC. Also, the surface activity/structure relationship revealed that carbonate cleavable surfactants with n-decyl group (CBAC10) showed the same behaviour as non-cleavable BAC. Furthermore, compounds containing n-octyl (CBAC8), n-decyl (CBAC10) and n-dodecyl (CBAC12) group showed strong antimicrobial activities.

New Classes of Polycationic Compounds as Preservatives for Ophthalmic Formulations.

PURPOSE: The purpose of this research work was to develop new polycationic compounds based on pyridine and piperidine structures with high antimicrobial activities against bacteria and fungi. Furthermore, the compounds should offer a lower toxicity than the commonly used preservatives for ophthalmic formulations, such as benzalkonium chloride (BAC) and polyquaternium-1 (PQ1). METHODS: Two polymers and three dimeric compounds were developed. Minimum inhibitory concentrations were determined for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis. The compounds were characterized regarding their impact on cell viability, cytotoxicity, epithelial integrity and surface tension. MTT and CytoTox-Glo™ assays, permeation studies with mannitol and transepithelial electrical resistance (TEER) measurements were performed on human corneal epithelial or MDCK I cells. BAC and PQ1 were used as references. RESULTS: Three polycationic compounds exhibited high antimicrobial activity against the tested microorganisms comparable to that of BAC. Four compounds were tolerated as well as or better than PQ1. In addition, the TEER, permeability and surface tension were only affected by compounds with amphiphilic properties. CONCLUSION: The pyridine- and piperidine-based polycationic compounds are promising candidates as new preservatives for ophthalmic formulations. Their high antimicrobial efficacy and good tolerability indicate a different mechanism of action compared to BAC.

Synthesis, Structure and Antimicrobial Properties of Novel Benzalkonium Chloride Analogues with Pyridine Rings.

Quaternary ammonium compounds (QACs) are a group of compounds of great economic significance. They are widely used as emulsifiers, detergents, solubilizers and corrosion inhibitors in household and industrial products. Due to their excellent antimicrobial activity QACs have also gained a special meaning as antimicrobials in hospitals, agriculture and the food industry. The main representatives of the microbiocidal QACs are the benzalkonium chlorides (BACs), which exhibit biocidal activity against most bacteria, fungi, algae and some viruses. However, the misuses of QACs, mainly at sublethal concentrations, can lead to an increasing resistance of microorganisms. One of the ways to avoid this serious problem is the introduction and use of new biocides with modified structures instead of the biocides applied so far. Therefore new BAC analogues P13-P18 with pyridine rings were synthesized. The new compounds were characterized by NMR, FT-IR and ESI-MS methods. PM3 semiempirical calculations of molecular structures and the heats of formation of compounds P13-P18 were also performed. Critical micellization concentrations (CMCs) were determined to characterize the aggregation behavior of the new BAC analogues. The antimicrobial properties of novel QACs were examined by determining their minimal inhibitory concentration (MIC) values against the fungi Aspergillus niger, Candida albicans, Penicillium chrysogenum and bacteria Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa. The MIC values of N,N-dimethyl-N-(4-methylpyridyl)-N-alkylammonium chlorides for fungi range from 0.1 to 12 mM and for bacteria, they range from 0.02 to 6 mM.

Preparation of benzalkonium salts differing in the length of a side alkyl chain.

Benzalkonium salts are widely used as disinfectants, biocides and detergents,among a variety of other applications. The cationic surface-activity of these salts determines their potential to act as a biocide on both target and non-target organisms. In this study, a quick synthesis of a complete set of the benzalkonium salts differing in the length of an alkylating chain (from C(2) to C(20)) is described. Moreover, their (1)H-NMR, HPLC-MS, TLC and HPLC analysis were recorded.

Soft antimicrobial agents: synthesis and activity of labile environmentally friendly long chain quaternary ammonium compounds.

A series of soft quaternary ammonium antimicrobial agents, which are analogues to currently used quaternary ammonium preservatives such as cetyl pyridinium chloride and benzalkonium chloride, were synthesized. These soft analogues consist of long alkyl chain connected to a polar headgroup via chemically labile spacer group. They are characterized by facile nonenzymatic and enzymatic degradation to form their original nontoxic building blocks. However, their chemical stability has to be adequate in order for them to have antimicrobial effects. Stability studies and antibacterial and antiviral activity measurements revealed relationship between activity, lipophilicity, and stability. Their minimum inhibitory concentration (MIC) was as low as 1 microg/mL, and their viral reduction was in some cases greater than 6.7 log. The structure-activity studies demonstrate that the bioactive compounds (i.e., MIC for Gram-positive bacteria of <10 microg/mL) have an alkyl chain length between 12 and 18 carbon atoms, with a polar headgroup preferably of a small quaternary ammonium group, and their acquired inactivation half-life must be greater than 3 h at 60 degrees C.

Thymine dimer formation as a probe of the path of DNA in and between nucleosomes in intact chromatin.

Photo-induced thymine dimer formation was used to probe nucleosome structure in nuclei. The distribution of thymine dimers in the nucleosome and recent studies of the structure of thymine dimer-containing DNA suggest that the rate of thymine dimer formation is affected by the direction and degree of DNA bending. This premise was used to construct a model of the path of DNA in the nucleosome, which has the following features. (i) There are four regions of sharp bending, two which have been seen previously by x-ray crystallography of the core particle. (ii) The DNA in H1-containing nucleosomes deviates from its superhelical path near the midpoint; this is not seen with H1-stripped chromatin. (iii) The internucleosomal (linker) DNA appears to be relatively straight.

Enteric neuronal ablation: structure-activity relationship in a series of alkyldimethylbenzylammonium chlorides.

Serosal application of a commercial solution of benzalkonium chloride (BAC) has been shown to selectively ablate myenteric neurons in the rat jejunum. This experimental model has proven useful in the study of the role of the myenteric plexus in intestinal function. The commercial BAC is a mixture of at least three homologous N-alkyldimethylbenzylammonium chlorides (ADBAC). The purpose of this study was to determine neuronal ablative activity in a series of ADBAC homologs when applied on the serosa of rat jejunum. Homologs not commercially available were synthesized and purified. Seven ADBAC homologs with alkyl chain lengths ranging from C6 to C18 were tested. A solution of each homolog (2 mM in saline) was applied directly on the serosa of an exteriorized portion of jejunum from anesthetized rats. Fifteen days after treatment, animals were sacrificed and treated tissues were processed for neuronal cell counts and muscle thickness determinations. All ADBAC homologs, except C18, ablated neurons of the myenteric plexus and produced thickening of intestinal smooth muscle. The number of submucosal neurons was not affected by any of the homologs. The structure-activity relationship observed in this study paralleled that of the reported antimicrobial activity of the ADBAC homologs, and is related to the aqueous solubility and relative surface activities of the homologs. The C14 homolog was found to be the most effective ablative agent, and reduced the number of myenteric neurons in a concentration-dependent manner. Thus, the C14 homolog can be used to produce a selectively denervated jejunal model for use in acute or chronic in vitro or in vivo studies of intestinal function.