Colloidal and antibacterial properties of novel triple-headed, double-tailed amphiphiles: exploring structure-activity relationships and synergistic mixtures.

Two novel series of tris-cationic, tripled-headed, double-tailed amphiphiles were synthesized and the effects of tail length and head group composition on the critical aggregation concentration (CAC), thermodynamic parameters, and minimum inhibitory concentration (MIC) against six bacterial strains were investigated. Synergistic antibacterial combinations of these amphiphiles were also identified. Amphiphiles in this study are composed of a benzene core with three benzylic ammonium bromide groups, two of which have alkyl chains, each 8-16 carbons in length. The third head group is a trimethylammonium or pyridinium. Log of critical aggregation concentration (log[CAC]) and heat of aggregation (ΔHagg) were both inversely proportional to the length of the linear hydrocarbon chains. Antibacterial activity increases with tail length until an optimal tail length of 12 carbons per chain, above which, activity decreased. The derivatives with two 12 carbon chains had the best antibacterial activity, killing all tested strains at concentrations of 1-2µM for Gram-positive and 4-16µM for Gram-negative bacteria. The identity of the third head group (trimethylammonium or pyridinium) had minimal effect on colloidal and antibacterial activity. The antibacterial activity of several binary combinations of amphiphiles from this study was higher than activity of individual amphiphiles, indicating that these combinations are synergistic. These amphiphiles show promise as novel antibacterial agents that could be used in a variety of applications.

The antibacterial activity of 4,4'-bipyridinium amphiphiles with conventional, bicephalic and gemini architectures.

Dialkyl 4,4'-bipyridinium compounds are widely employed for their useful redox properties, and are commonly known as viologens due to their intense coloration upon reduction. Despite their prevalence and amphiphilic nature, the antibacterial activity of these compounds remains largely unreported. We have thus prepared a series of mono- and bis-alkylated analogs of 4,4'-bipyridine to investigate structure-activity relationships in their inhibition of a battery of Gram positive and Gram negative bacteria. The prepared cationic compounds were conventional (one cationic head, one non-polar tail), bicephalic (two heads, one tail), or gemini (two heads, two tails) in their amphiphilic structure. Additionally, an isomeric series of six bis-alkylated compounds ranging from symmetric (PQ-11,11) to highly asymmetric (PQ-20,2) were prepared. Four themes of bioactivity emerged: (1) the most bioactive compounds were gemini in structure; (2) 22 carbons in the alkyl chains, with little to modest asymmetry, led to optimal activity; (3) bicephalic compounds were generally comparable to conventional amphiphiles, though only about 12 carbons in the alkyl chains were solubilized in water by each cationic nitrogen; (4) the effects of counterion identity were not evident between chlorides and bromides; however, the presence of the iodide counterion inhibited dissolution in all compounds tested. Three isomeric compounds with little to no asymmetry in tail length, PQ-11,11, PQ-12,10, and PQ-14,8, prepared as the bromide salts, showed comparable and highly potent activity, with MIC levels around 2 µM against 3 of 4 bacteria tested. The simple (one- to two-step) syntheses of potent antimicrobials portend well for future optimization.

Hydra amphiphiles: Using three heads and one tail to influence aggregate formation and to kill pathogenic bacteria.

Hydra amphiphiles mimic the morphology of the mythical multi-headed creatures for which they are named. Likewise, when faced with a pathogenic bacterium, some hydra derivatives are as destructive as their fabled counterparts were to their adversaries. This report focuses on eight new tricephalic (triple-headed), single-tailed amphiphiles. Each amphiphile has a mesitylene (1,3,5-trimethylbenzene) core, two benzylic trimethylammonium groups and one dimethylalkylammonium group with a linear hydrophobe ranging from short (C8H17) to ultralong (C22H45). The logarithm of the critical aggregation concentration, log(CAC), decreases linearly with increasing tail length, but with a smaller dependence than that of ionic amphiphiles with fewer head groups. Tail length also affects antibacterial activity; amphiphiles with a linear 18 or 20 carbon atom hydrophobic chain are more effective at killing bacteria than those with shorter or longer chains. Comparison to a recently reported amphiphilic series with three heads and two tails allows for the development of an understanding of the relationship between number of tails and both colloidal and antibacterial properties.

Heterodimerization studies of calix[4]arene derivatives in polar solvents.

[reaction: see text] Several calix[4]arene derivatives propylated on the lower rim and substituted on the upper rim with amino or carboxyl groups have been synthesized. Examples include calixarenes substituted with alanino (C- and N-linked), amino, carboxy, carboxyphenyl, and amidino groups. The self-assembly of these derivatized calixarenes into heterodimers has been studied by NMR in DMSO-d(6) or CD(3)OD with 5% aqueous phosphate buffer.

Chemical Reaction between Colliding Vesicles.

An organic reaction between two populations of vesicles, one containing a nucleophile (blue) and the other an electrophile (red), was examined kinetically. By comparing the rates with those of suitable controls, it was demonstrated that the electrophile is transferred during vesicle collisions, and a fast intra-vesicular reaction ensues.

Bicephalic amphiphile architecture affects antibacterial activity.

A series of cationic amphiphiles, each with an aromatic core, was prepared and investigated for antimicrobial properties. The synthesized amphiphiles in this study are bicephalic (double-headed) in that they each possess two trimethylammonium head groups and a single linear alkoxy tail. Minimum inhibitory and minimum bactericidal concentrations of these amphiphiles were in the low micromolar range. Antimicrobial activities are highly sensitive to the chain length of the hydrophobic region, and modestly reliant on the relative positioning of the head groups on the aromatic core. These trends were more pronounced in time kill assays, wherein longer chain compounds required significantly shorter times to completely kill bacteria. Microscopy suggested that the mode of cell death was lysis. Strong inhibition was observed with both biscationic compounds and monocationic comparisons against Gram-positive bacteria; only biscationic amphiphiles maintained good activity versus the Gram-negative bacteria tested. These observations provide direction for future antimicrobial structural investigations.

Biscationic bicephalic (double-headed) amphiphiles with an aromatic spacer and a single hydrophobic tail.

We report the synthesis and aggregation studies of a homologous family of biscationic "bicephalic" amphiphiles. Each of has a linear alkoxy chain and two trimethylammonium bromide headgroups connected to a benzene ring. Krafft temperatures (T(K)) in water were determined by differential scanning calorimetry (DSC) and conductivity. Critical micelle concentration (cmc) and ionization degree (alpha) values were determined by monitoring the conductivity of aqueous solutions as a function of concentration, and confirmed by monitoring the (1)H NMR chemical shift of the terminal methyl group as a function of concentration. Values for log(cmc) decrease linearly with increasing chain length, with a smaller dependence on chain length than for single-headed amphiphiles, consistent with literature reports on other bicephalic amphiphiles. Comparison to two related amphiphiles, each with a single headgroup reveals that the addition of a second head group results in an increase in cmc and a decrease of T(K). These effects are attributed to greater water solubility due to the incorporation of a second, hydrophilic headgroup. The effect on alpha is also discussed.

Self-assembled thermoreversible gels of nonpolar liquids by racemic propargylic alcohols with fluorinated and nonfluorinated aromatic rings.

The synthesis and colloidal study of a new class of low molecular weight organogelators is reported. Racemic propargylic alcohols with perfluoroaryl and nonfluorinated aryl rings are capable of forming gels in alkane liquids and/or silicone oil. A full colloidal characterization of alkane gels prepared from (R/S)-1-pentafluorophenyl-3-phenylprop-2-yn-1-ol [(R/S)- 1] was conducted, including both structural [optical microscopy, scanning electron microscopy (SEM), powder X-ray diffraction (XRD), attenuated total reflectance infrared spectroscopy (ATR-IR)] and thermal stability [differential scanning calorimetry (DSC)] studies. A model of the organization of gelator molecules within gel fibers has been proposed primarily based on the correlation of diffraction data for the powder XRD pattern of a gel and a simulated powder pattern from a sublimed crystal of the gelator. Furthermore, structural requirements for propargylic alcohol gelators were investigated by subjecting derivatives with modified structures to gelation tests. An enantiomerically enriched sample [(R)- 1, 83% ee] fails to entrap the solvent under conditions where the racemate successfully forms a gel. The remaining racemic derivatives (with p-alkoxy or p-alkyl substituents on the nonfluorinated arene) form gels or partial gels in silicone oil and in some alkane preparations.

Depth-profiling with giant vesicle membranes.

A phospholipid fluorescent-labeled in one of three locations was paired with a phospholipid labeled with a quencher in one of three locations within a host phospholipid bilayer. The various combinations of quenching efficiencies allowed the location of the fluorescent labels to be determined. It was found that all three labels (including one attached to the chain terminus) position themselves at the bilayer surface. The tendency of even modestly polar molecules (or sections of molecules) to gravitate to the membrane surface has numerous practical ramifications.

Gemini-induced columnar jointing in vitreous ice. Cryo-HRSEM as a tool for discovering new colloidal morphologies.

A gemini surfactant is able to promote columnar jointing in vitreous ice where long pillars, often of hexagonal cross section, are formed. This jointing is visible by cryo-high-resolution scanning electron microscopy (cryo-HRSEM), in which colloidal suspensions in bulk water are cooled rapidly in liquid ethane, thereby avoiding the potential artifacts with other types of EM. The jointing is proposed to arise from a new type of colloidal morphology where the surfactant self-assembles into hexagonal columns. Evidence for this mechanism comes from a cryo-HRSEM photo of an ice-free hexagonal "skeleton" composed of surfactant. Cryo-HRSEM, a method that is just beginning to realize its potential, would seem to have a promising future in the discovery of additional and as yet unimagined colloidal structures.