Gemini Compounds Research Articles

Anti-adhesive, anti-biofilm and fungicidal action of newly synthesized gemini quaternary ammonium salts

Newly synthesized gemini quaternary ammonium salts (QAS) with different counterions (bromide, hydrogen chloride, methylcarbonate, acetate, lactate), chain lengths (C12, C14, C16) and methylene linker (3xCH2) were tested. Dihydrochlorides and dibromides with 12 carbon atoms in hydrophobic chains were characterized by the highest biological activity against planktonic forms of yeast and yeast-like fungi. The tested gemini surfactants also inhibited the production of filaments by C. albicans. Moreover, they reduced the adhesion of C. albicans cells to the surfaces of stainless steel, silicone and glass, and slightly to polystyrene. In particular, the gemini compounds with 16-carbon alkyl chains were most effective against biofilms. It was also found that the tested surfactants were not cytotoxic to yeast cells. Moreover, dimethylcarbonate (2xC12MeCO3G3) did not cause hemolysis of sheep erythrocytes. Dihydrochlorides, dilactate and diacetate showed no mutagenic potential.

Adsorption and Aggregation Behavior of Mixtures of Quaternary-Ammonium-Salt-Type Amphiphilic Compounds with Fluorinated Counterions and Surfactants.

The surface adsorption and aggregation behavior of a mixture of quaternary-ammonium-salt-type amphiphilic monomeric compounds (C4 FSA, C8 FSA, and C4 NTf2) or gemini compounds (C10-2-C4 FSA) and various surfactants (nonionic hexaoxyethylene dodecyl ether (C12EO6), anionic sodium dodecyl sulfate (SDS), cationic dodecyltrimethylammonium bromide (C12TAB), and zwitterionic N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (C12Sb)) was investigated. Both types of compounds contained alkyl chains of nonidentical lengths that used bis(fluorosulfonyl)imide (FSA-) or bis(trifluoromethanesulfonyl)imide (NTf2-) as counterions. The mixtures were analyzed for surface tension, viscosity, electrical conductivity, and pyrene fluorescence, in addition to evaluation by cryogenic transmission electron microscopy, small-angle X-ray scattering, and dynamic light scattering. Our results showed that the surface tension depended on the surfactant structure. For the mixture of C8 FSA and SDS, as the SDS concentration increased, the surface tension first decreased and became constant at the critical micelle concentration (CMC). In this concentration range, C8 FSA and SDS were approximately equimolar (2.5 mmol dm-3), the mixture adsorbed efficiently at the air-water interface, and vesicles and linear-type micelles were formed in the solution owing to the decreased electrostatic repulsion between the hydrophilic groups. As the SDS concentration further increased, the surface tension increased and reached another constant value. The C8 FSA at the interface was replaced by SDS and the aggregates transformed into spherical micelles. The surface tension plot of the mixture of the amphiphilic compounds and C12Sb showed a minimum at the CMC. The lowest CMC and surface tension were observed for C10-2-C4 FSA, indicating that the gemini compounds offer excellent adsorption and orientation at the air-water interface. It was revealed that the quaternary-ammonium-salt-type amphiphilic compounds in this study acted as ionic liquids on their own and as surfactants in aqueous solution. Further, they could improve the surface activity of conventional ionic surfactants.

Synthesis and surface‐active properties of novel cleavable gemini surfactants

AbstractA novel series of quaternary ammonium gemini compounds having a butynylene spacer and different hydrocarbon chain lengths (CGBu8‐16) were prepared. Carbonate group inserted between the hydrocarbon chains and the polar heads make these compounds hydrolyzable. The degradation under hydrolysis of these novel series will lead to the generation of fatty alcohols and readily degradable compounds. The reagents used are biodegradable, renewable, or reusable. The surface activities and foamability in aqueous solution of the cleavable gemini compounds containing n‐octyl, n‐decyl, and n‐dodecyl chains meet the criteria for being good surfactants and showed stable foams even at low concentrations.

Physicochemical and solution properties of quaternary-ammonium-salt-type amphiphilic gemini ionic liquids with spacers containing oxygen or nitrogen

Quaternary-ammonium-salt-type amphiphilic gemini compounds 2Cn(Spacer) NTf2 were synthesized by the quaternization of a tertiary diamine and an n-alkyl bromide, followed by an ion-exchange reaction with potassium bis(trifluoromethanesulfonyl)imide [(Spacer) = (2-O-2), (2-O-2-O-2), (2-N-2), (2/2-N-2), (2/2)-OH, (5), (6), and n represents the alkyl chain lengths; n = 10, 12, 14 for the 2-O-2 spacer, and n = 12 for all others]. The compounds with melting points below 100 °C were treated as ionic liquids during the subsequent measurements. The melting points of the amphiphilic gemini compounds could be arranged in the following order, based on the spacer present: (2/2)-OH >> 2/2-N-2 > (2-N-2) > (2-O-2) > (5) > (6) > (2-O-2-O-2). The melting points for 2Cn(2-O-2) NTf2 (n = 10, 12), 2C12(2-O-2-O-2) NTf2, and 2C12(2-N-2) NTf2 could be reduced to <0 °C. The amphiphilic gemini ionic liquids exhibited significantly lower conductivities and higher viscosities than the corresponding monomeric ionic liquids. This was attributed to a decrease in the mobility of the cationic molecules caused by the gemini structure, in which the two monomeric compounds are connected by a spacer. Furthermore, the amphiphilic gemini ionic liquids, particularly those containing oxygen in the spacer, exhibited efficient adsorption at the air/water interface.

The influence of the Gemini surfactants hydrocarbon tail on in-situ synthesis of silver nanoparticles: Characterization, surface studies and biological performance

Three different Gemini compounds containing different lengths of multi-carbonyl groups were synthesized, and the effect of their hydrocarbon tail length on the AgNPs synthesis was investigated. The Gemini surfactants with the long hydrocarbon chain tail produces small AgNPs with a narrow size distribution and high colloidal stability in an aqueous phase. The surface parameters of the aqueous solution were affected by the hydrocarbon chain length as well as phase temperature. The critical micelle concentration, assessed by surface tension and conductometric measurements, decreases with both increasing solution temperature and increasing hydrocarbon tail length. Thermodynamic calculations predicted the ability of the synthesized Gemini surfactant to adsorb on the phase surface and aggregate in a cluster.

Synthesis of Gemini analogs of 19-norcalcitriol and their platinum(II) complexes

Hormonally active vitamin D3 metabolite, calcitriol, plays an important role in calcium-phosphate homeostasis, immune system actions and cell differentiation. Although anticancer activity of calcitriol is well documented and thousands of its analogs have been synthesized, none has been approved as a potential drug against cancer. Therefore, we attempted to introduce the cytotoxic effect to the calcitriol molecule by its linking to cisplatin. Herein, we present the synthesis of vitamin D compounds, designed on the basis of molecular modeling and docking experiments to the vitamin D receptor, and characterized by the presence of significantly different two side chains attached to C-20. In this study, a new synthetic approach to Gemini analogs was developed. Preparation of the target 19-norcalcitriol compounds involved separate syntheses of several building blocks (the A-ring, C/D-rings and side-chain fragments). The convergent synthetic strategy was used to combine these components by the different coupling processes, the crucial one being Wittig-Horner reaction of the Grundmann ketone analog with the known 2-methylene A-ring phosphine oxide. Due to the nature of the constructed steroidal side chains (bidentate ligands), which allowed coordination of metal ions, the first conjugate-type platinum(II) complexes of the vitamin D analogs were also successfully prepared and characterized. The target vitamin D compounds, displaying significant affinity for a vitamin D receptor, were assessed in vitro for their anti-proliferative activities towards several cell lines.

Characterization and Solution Properties of Quaternary-Ammonium-Salt-Type Amphiphilic Gemini Ionic Liquids

Quaternary-ammonium-salt-type amphiphilic gemini compounds (Cm-2-Cn X, where m and n represent the alkyl chain lengths; m = 4, 6, 8, 10; n = 2, 4, 6, 8, 10; m ≥ n; and X indicates the counterion BF4, PF6, OTf, FSA, or NTf2) were synthesized by the quaternization of N,N,N′,N′-tetramethylethylenediamine and n-alkyl bromide and a subsequent ion-exchange reaction with five different counterions. For comparison, the corresponding monomeric compounds (Cn X, n = 2, 4, 6, 8, and 10) were also synthesized. The melting points of the compounds were evaluated using differential scanning calorimetry, and those with melting points lower than 100 °C were treated as ionic liquids during the subsequent measurements. The amphiphilic gemini compounds exhibited the lowest melting points (44–49 °C) when bulky NTf2– was the counterion and the degree of dissymmetry between the two alkyl chains was 0.4 < n/m < 0.75. However, their melting points were not similar to those of the monomeric compounds with NTf2– and n = 4–10 (<29 °C). The gemini ionic liquids exhibited significantly lower conductivities and higher viscosities than those of the corresponding monomeric ionic liquids. This is because of the decrease in the mobility of the cation molecules caused by the gemini structure, in which the two monomeric compounds are connected by a spacer. The gemini ionic liquids also showed higher densities than those of the corresponding monomeric ionic liquids, owing to the dimer of the gemini structure. Further, the gemini ionic liquids were adsorbed readily at the air/water interface and oriented themselves but did not show the critical micelle concentration for the concentration range over which they could be dissolved in water. The amphiphilic monomeric and gemini ionic liquids also tended to form ion pairs in aqueous solutions, as the length of their alkyl chain was relatively short.

Activity-Structure Study on the Peptide Fraction of AG2: a Potent In Vitro Transfection Agent.

Gemini-based amphiphiles are candidates for biomedical applications. In fact, most of the gemini compounds described in the literature have been prepared to be used as new synthetic vectors in gene transfection. Our group carried out an activity-structure study starting from the structure of the gemini [AG2-C18/]2, which is an effective in vitro transfection reagent. We synthesized a series of novel amphiphilic amino acid derivatives of low molecular weight, named AGn-Cm (N), in which the same apolar region (m) of oleic or palmitic acid was maintained and the peptide region was modified by amino acid insertions, deletions, and substitutions. We also determined the transfection efficiency, critical micelle concentration, particle size, and ζ-potential for these derivatives. Amphiphiles AG10-C16 and AG10-C18 were more active at a lower N/P ratio than AG2-C18. These amphiphiles showed no activity when lysine was replaced by ornithine, and the activity of all derivatives increased when there were more ornithine residues and a W/O = 1 ratio in the peptide region. It can be said that for AG10-C16, these two structural requirements on the amino acid portion predominated over the type of aliphatic chain used.

Cationic gemini compounds with antifungal activity and wood preservation potentiality

Three gemini compounds were synthesized and characterized in the search of an alternative eco-friendly wood preservative. Synthesis was carried out from N,N-dimethylamines and 2-O-acetyl-1,3- dichloropropane as linker molecule. All the synthesized molecules were adequately purified and characterized by TLC, GC, FT-IR and NMR. Their tensioactive properties were determined. All three efficiently lowered the surface tension in aqueous solutions with critical micelle concentrations ranging from 0.53 to 1.34mM. Their antifungal activities were evaluated from a broth dilution test against four yeasts and two filamentous fungi and were compared to commercially available references: Fluconazole and TCMTB (2-thiocyanomethylthiobenzothiazole). All gemini compounds displayed good antifungal activity; particularly, the gemini derived from N,N-dimethyldodecylamine, with even better performance than Fluconazole against Saccharomyces cerevisiae, Aspergillus niger and Alternaria sp., and than TCMTB against the last one. The environmental impact of the gemini compound that showed the highest antifungal activity was analyzed through ecotoxicity tests, using Chlorella vulgaris and Daphnia magna as model organisms. It was several orders of magnitude less toxic than TCMTB. Finally, wood preservation efficacy studies were carried out on pine (Pinus ponderosa) samples. Results demonstrated accomplished resistance against brown rot fungi, comparable to a widespread commercial hydrosoluble preservative.

Viability, Enzymatic and Protein Profiles of Pseudomonas aeruginosa Biofilm and Planktonic Cells after Monomeric/Gemini Surfactant Treatment.

This study set out to investigate the biological activity of monomeric surfactants dodecyltrimethylammonium bromide (DTAB) and the next generation gemini surfactant hexamethylene-1,6-bis-(N,N-dimethyl-N-dodecylammonium bromide) (C6) against the environmental strain Pseudomonas aeruginosa PB_1. Minimal inhibitory concentrations (MIC) were determined using the dilution method. The viability of the planktonic cells and biofilm was assessed using the plate count method. Enzymatic profile was determined using the API-ZYM system. Proteins were extracted from the biofilm and planktonic cells and analysed using SDS-PAGE. The MIC of the gemini surfactants was 70 times lower than that of its monomeric analogue. After 4 h of treatment at MIC (0.0145 mM for C6 and 1.013 mM for DTAB), the number of viable planktonic cells was reduce by less than 3 logarithm units. At the concentration ≥MIC, a reduction in the number of viable cells was observed in mature biofilms (p < 0.05). Treatment for 4 h with gemini surfactant at 20 MIC caused complete biofilm eradication. At sub-MIC, the concentration of some enzymes reduced and their protein profiles changed. The results of this study show that due to its superior antibacterial activity, gemini compound C6 can be applied as an effective microbiocide against P. aeruginosa in both planktonic and biofilm forms.

Action of Monomeric/Gemini Surfactants on Free Cells and Biofilm of Asaia lannensis.

We investigated the biological activity of surfactants based on quaternary ammonium compounds: gemini surfactant hexamethylene-1,6-bis-(N,N-dimethyl-N-dodecylammonium bromide) (C6), synthesized by the reaction of N,N-dimethyl-N-dodecylamine with 1,6-dibromohexane, and its monomeric analogue dodecyltrimethylammonium bromide (DTAB). The experiments were performed with bacteria Asaia lannensis, a common spoilage in the beverage industry. The minimal inhibitory concentration (MIC) values were determined using the tube standard two-fold dilution method. The growth and adhesive properties of bacterial cells were studied in different culture media, and the cell viability was evaluated using plate count method. Both of the surfactants were effective against the bacterial strain, but the MIC of gemini compound was significantly lower. Both C6 and DTAB exhibited anti-adhesive abilities. Treatment with surfactants at or below MIC value decreased the number of bacterial cells that were able to form biofilm, however, the gemini surfactant was more effective. The used surfactants were also found to be able to eradicate mature biofilms. After 4 h of treatment with C6 surfactant at concentration 10 MIC, the number of bacterial cells was reduced by 91.8%. The results of this study suggest that the antibacterial activity of the gemini compound could make it an effective microbiocide against the spoilage bacteria Asaia sp. in both planktonic and biofilm stages.

Surface-active properties of new cationic gemini surfactants with cyclic spacer

ABSTRACTThree cationic gemini surface active compounds of the type (1r,4r)-1,4-dialkyl-1,4-dimethy-l-piperazine-1,4-diium bromide (Ia, Ib, and Ic), were synthesized. They were characterized using elemental analysis and 1H-NMR spectra. Their surface-active properties were measured in aqueous solutions with different concentrations at different temperatures (25, 40, and 55°C). Various surface measurements of these gemini surfactants, (compared to the conventional one, 1-Dodecyl-1-methylpiperidinium bromide (a)) were estimated, specifically critical micelle concentration (CMC), effectiveness (πCMC), efficiency (PC20) as well as maximum surface excess (Γmax) and minimum surface area (Amin). The measurements of the gemini compounds gave low CMC, high efficiency in reducing the surface tension, and intense adsorption at air/water interface. These surfactants have lower Krafft points and thus better solubility. Thermodynamic data, free energy, entropy, and enthalpy changes (ΔG°, ΔS°, and ΔH°) for micellization at the air/water interface and also for adsorption in the bulk of surface-active solutions were calculated.

Structural analysis and biological activities of BXL0124, a gemini analog of vitamin D

Gemini analogs of calcitriol, characterized by the extension of the C21-methyl group of calcitriol with a second chain, act as agonists of the vitamin D receptor (VDR). This second side chain of gemini is accommodated in a new cavity inside the VDR created by the structural rearrangement of the protein core. The resulting conformational change preserves the active state of the receptor and bestows gemini compounds with biological activities that exceed those of calcitriol. Of particular interest are gemini’s anti-cancer properties, and in this study we demonstrate anti-proliferative and tumor-reducing abilities of BXL0124 and BXL0097, differing only by the presence or absence, respectively, of the methylene group on the A ring. BXL0124 acts as a more potent VDR agonist than its 19-nor counterpart by activating VDR-mediated transcription at lower concentrations. In a similar manner, BXL0124 is more active than BXL0097 in growth inhibition of breast cancer cells and reduction of tumor volume. Structural comparisons of BXL0097 and BXL0124, as their VDR complexes, explain the elevated activity of the latter.

Self-organization and solubilization properties of gemini hydrotropic compounds in aqueous solution

A series of amidoamine derivatives composed of two amphiphilic units linked with alkyl spacers varying in length was synthesized. The amphiphilic unit consisted of a quaternary ethylammonium headgroup, 14 carbon atoms in the tail and an amide group placed in-between. The aggregation properties of the gemini compounds were examined by tensiometric, conductometric and spectroscopic methods and compared with the properties of their single-tail analogue. In spite of structural relation to gemini surfactants, some significant changes in solution behaviour, in comparison to typical surfactants and previously described gemini surfactants, were found. Most of the compounds within the obtained series aggregated to very small associates rather than to the typical micelles formed by gemini amphiphiles at very low concentrations. The size of aggregates obtained from dynamic light scattering measurements was confirmed by cryo-TEM visualization of the studied assemblies which contained only a few molecules. The size of aggregates and very low aggregation number indicated similarity of the studied compounds to hydrotropes which, despite their amphiphilic structure, do not form micelles. The influence of spacer length on the solution behaviour of geminis was discussed. The solubilization studies of Sudan I showed that the solubility of the hydrophobic dye in water is high at very small concentrations of the studied compounds, significantly smaller than in the case of their single-tail analogue.

Influence of the Chemical Structure of Gemini Quaternary Ammonium Compounds on Copper Electrodeposition

Two series of cationic gemini compounds have been studied with respect to electrochemical and via filling behaviors in copper electrodeposition. They include linear and pyridinium gemini series. The investigation focuses on the structural aspect of the spacer and the hydrophobic tails of the geminis. The electrochemical and via filling behaviors of the geminis are strongly influenced by their chemical structure. The type and the length of the spacer of geminis are of major importance for their suppressing capability and the via filling behavior. Gemini molecules response to SPS (bis(3-sulfopropyl) disulfide) shows structure dependence. The change of Δη (the potential difference obtained from different rotational speed) values of the geminis upon adding SPS depends mainly on the structure of the hydrophobic tails of the gemini molecules. SPS may improve the via filling behavior for the geminis with flexible hydrophobic tails, while it may lead to a reduced via filling activity for those with the rigid hydrophobic tails. Potential oscillation in the galvanostatic experiment can be associated with the rigidity of the hydrophobic tails of geminis.

Efficacies of Novel Gemini Compounds Derived from Dibasic Acids as Multifunctional Additives for Tribological Applications

A series of new gemini compounds derived from the reaction of dibasic acids with N,N-diethyl-2-aminoethanol followed by reaction with p-toluene sulfonic acid were synthesized and characterized by means of Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance technique (1H NMR), and mass spectral analyses. The synthesized compounds were used as multifunctional additives, particularly as antiwear agents, as friction reducing agents, and as corrosion inhibitors for tribological applications. To the best of our knowledge, this is the first report describing the use of gemini compounds in tribological applications.

Multi‐stage tandem mass spectrometric analysis of novel β‐cyclodextrin‐substituted and novel bis‐pyridinium gemini surfactants designed as nanomedical drug delivery agents

This study aimed at evaluating the collision-induced dissociation tandem mass spectrometric (CID-MS/MS) fragmentation patterns of novel β-cyclodextrin-substituted- and bis-pyridinium gemini surfactants currently being explored as nanomaterial drug delivery agents. In the β-cyclodextrin-substituted gemini surfactants, a β-cyclodextrin ring is grafted onto an N,N-bis(dimethylalkyl)-α,ω-aminoalkane-diammonium moiety using variable succinyl linkers. In contrast, the bis-pyridinium gemini surfactants are based on a 1,1'-(1,1'-(ethane-1,2-diylbis(sulfanediyl))bis(alkane-2,1-diyl))dipyridinium template, defined by two symmetrical N-alkylpyridinium parts connected through a fixed ethane dithiol spacer. Detection of the precursor ion [M](2+) species of the synthesized compounds and the determination of mass accuracies were conducted using a QqTOF-MS instrument. A multi-stage tandem MS analysis of the detected [M](2+) species was conducted using the QqQ-LIT-MS instrument. Both instruments were equipped with an electrospray ionization (ESI) source. Abundant precursor ion [M](2+) species were detected for all compounds at sub-1 ppm mass accuracies. The β-cyclodextrin-substituted compounds, fragmented via two main pathways: Pathway 1: the loss of one head-tail region produces a [M-(N(Me)2-R)](2+) ion, from which sugar moieties (Glc) are sequentially cleaved; Pathway 2: both head-tail regions are lost to give [M-2(N(Me)2-R)](+), followed by consecutive loss of Glc units. Alternatively, the cleavage of the Glc units could also have occurred simultaneously. Nevertheless, the fragmentation evolved around the quaternary ammonium cations, with characteristic cleavage of Glc moieties. For the bis-pyridinium gemini compounds, they either lost neutral pyridine(s) to give doubly charged ions (Pathway A) or formed complementary pyridinium alongside other singly charged ions (Pathway B). Similar to β-cyclodextrin-substituted compounds, the fragmentation was centered on the pyridinium functional groups. The MS(n) analyses of these novel gemini surfactants, reported here for the first time, revealed diagnostic ions for each compound, with a universal fragmentation pattern for each compound series. The diagnostic ions will be employed within liquid chromatography (LC)/MS/MS methods for screening, identification, and quantification of these compounds within biological samples.

双性イオンジェミニ型化合物のイオン特性を活用した毛髪吸着性とケア効果の向上

双性イオンジェミニ型化合物のイオン特性を活用した毛髪吸着性とケア効果の向上

OneF-Octyl versus TwoF-Butyl Chains in Surfactant Aggregation Behavior

An easy synthetic procedure in two or three steps from perfluoroalkylethyl iodide derivatives led to six novel fluorinated carboxylates monomeric and gemini surfactants with one or two hydrophobic tails, respectively: RF(C2H4)CH(CO2(-))2,2Na(+) and [RF(C2H4)]2C(CO2(-)),Na(+), where RF = C4F9, C6F13, and C8F17. These anionic surfactants exhibited very low surface tension from 15 to 33 mN/m as well as low critical micelle concentration until 1.3 × 10(-4) mol/L. Furthermore, the surface properties of the gemini compound with two short fluoroalkyl chains (RF = C4F9) were found to be almost equal to those of the monomeric surfactant with one long fluoroalkyl chain (RF = C8F17), which could provide an interesting alternative to the bioaccumulative long-chain perfluorinated surfactant.

Synthesis, Surface‐Active Properties, and Anthelmintic Activities of New Cationic Gemini Surfactants Against the Gastrointestinal Nematode, Heligmosomoides polygyrus bakeri, In Vitro

AbstractA novel series of cationic dimeric surfactants was prepared involving the ketalization reaction, Williamson etherification, and regioselective oxirane ring opening with tertiary alkyl amines. The synthesized compounds were obtained in high purity by a simple purification procedure using column chromatography. The critical micelle concentration (CMC), effectiveness of surface tension reduction (γCMC), surface excess concentration (Γ), and area per molecule at the interface (A) were determined and values indicate that the cationic series is characterized by good surface‐active and self‐aggregation properties. For the first time, we reported the anthelmintic activities against the rodent gastrointestinal nematode Heligmosomoides polygyrus bakeri, in vitro for cationic gemini compounds. In the series of five tested cationic compounds (4a–e), three of them (4a, 4b and 4d) were shown to have an excellent anthelmintic activity in vitro at different concentrations. The anthelmintic activity was found to be dependent on the type of cationic compound, concentration and incubation time. The cationic di‐C12 (4a) derivate of the series was the best anthelmintic agent, its use was optimal at a minimum concentration of 50 ppm and with 60 min of incubation.