Bis-quaternary Ammonium Compounds Research Articles

Synthesis and antibacterial activity of new bis-quaternary ammonium compounds based on polyhydric alcohol

Synthesis and antibacterial activity of new bis-quaternary ammonium compounds based on polyhydric alcohol

The synthesis of bisquaternary ammonium compounds (microreview)

The synthesis of bisquaternary ammonium compounds (microreview)

Microbiological Evaluation of Novel Bis-Quaternary Ammonium Compounds: Clinical Strains, Biofilms, and Resistance Study.

This work is devoted to the investigation of biocidal properties of quaternary ammonium compounds (QACs) based on pyridine structures with aromatic spacers, and their widely known analogs, against clinically significant microorganisms. This study is focused on investigating their antimicrobial activity (minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs)), antibiofilm properties (minimum biofilm inhibitory concentrations (MBICs) and minimum biofilm eradication concentrations (MBECs)), synergetic effect with different alcohols in antiseptic formulations, and bacterial resistance development. It was shown that all combined analogue preparations had a higher level of antibacterial activity against the tested bacterial strains, with a 16- to 32-fold reduction in MICs and MBCs compared to previously used antiseptic preparations. Moreover, hit-QACs demonstrated a stable effect against Gram-negative E. coli, K. pneumoniae, and A. baumannii within a month of incubation. Overall results indicated a high level of antibacterial activity of pyridine-based QACs.

Novel Phenyl‐Based Bis‐quaternary Ammonium Compounds as Broad‐Spectrum Biocides

Herein we report the synthesis and microbiological evaluation of novel phenyl based bis-quaternary ammonium compounds (bis-QACs). Using a simple 2-step synthetic route from dibromo- and dihydroxybenzenes, we obtained a structurally diverse broad panel of bis-QACs with topologically distinct bridging connections between pyridinium heads. Selected analogs possessed potent broad-spectrum biocidal activity against both bacterial and fungal pathogens: methicillin-resistant Staphylococcus aureus (ATCC 43300); Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Acinetobacter baumannii (ATCC 19606), Pseudomonas aeruginosa (ATCC 27853), Candida albicans (ATCC 90028), Cryptococcus neoformans var. grubii (ATCC 208821). Promising compounds displayed minimum inhibitory concentrations (MIC) values ≤0.25 μg/mL alongside improved cytotoxicity and hemolytic profiles compared to modern antiseptics. Thus, synthesized bis-QACs represent a promising class of biocides with the potential to replace existing household sanitizers.

Synthesis and biological evaluation of novel bis-quaternary ammonium compounds with p-terphenyl spacer

Novel bis-quaternary ammonium compounds with a p-terphenyl spacer between two pyridinium heads were synthesized. Hit compound with C8H17 aliphatic substituent is superior to known benzalkonium chloride, miramistin and chlorhexidine bisgluconate in MIC values against five pathogenic bacteria.

Synthesis and microbiological properties of novel bis-quaternary ammonium compounds based on 4,4′-oxydiphenol spacer

Novel gemini (tail–head–spacer–head–tail) bis-quaternary ammonium compounds with a 4,4′-oxydiphenol spacer between two pyridinium heads were synthesized and compared with commonly used antiseptics such as benzalkonium chloride and chlorhexidine gluconate. Analogues bearing C8H17, C9H19 and C10H21 aliphatic groups displayed potent broad spectrum in vitro activity against five bacterial strains and two fungi, with minimum inhibtory concentrations relatively independent of the counter ion.

A comparative study of skin irritation caused by novel bis-quaternary ammonium compounds and commonly used antiseptics by using cell culture methods

New bis-quaternary ammonium compounds (bis-QACs) 3-(3-hydroxy-2-(hydroxymethyl)-2-{[(1-dodecylpyridinium-3-yl)oxy]methyl}propoxy)-1-dodecylpyridinium dibromide (3HHDMP-12) and 3,3′-[1,4-phenylenebis(oxy)]bis(1-dodecylpyridinium) dibromide (3PHBO-12) were compared with commonly-used antiseptics such as benzalkonium chloride (BAC), octenidine dihydrochloride (OCT), chlorhexidine digluconate (CHG) and polyhexamethylene biguanide (PHMB), to evaluate their potential to cause skin irritation. The cytotoxicity of these compounds in various cultured cells, as well as their effect on the expression of inflammatory cytokine genes such as IL-1α were evaluated.The cytotoxic effect of these bis-QACs on several types of human-derived cells was lower than that of common quaternary ammonium compounds (BAC and OCT), although the bis-QACs showed higher cytotoxicity than the biguanide-based compounds (CHG and PHMB). In addition, IL-1α mRNA expression was more strongly induced by BAC and OCT than by the new bis-QACs, at concentrations below the IC50 obtained in normal human epidermal keratinocytes. Furthermore, even at the actual therapeutic concentration, the new bis-QACs did not alter inflammatory cytokine mRNA expression or IL-1α secretion as demonstrated using the reconstructed human epidermis model LabCyte EPI-MODEL.The results suggested that the potential of 3PHBO-12 and 3HHDMP-12 to induce skin irritation is comparable to or less than that of existing antiseptics, and these bis-QACs may be useful antiseptics with few side effects.

Steroidal Ammonium Compounds as New Neuromuscular Blocking Agents.

Neuromuscular blocking agents are widely used as an anesthesia auxiliary in surgery, which induce relaxation of skeletal muscles by blocking signal transmission at the neuromuscular junction. Many neuromuscular blocking agents s were developed over the past decades, but none of them fully meets the needs of the clinic by various reasons. In this study, a series of quaternary ammonium steroidal neuromuscular blocking agents were synthesized and evaluated on isolated mouse phrenic nerve-hemidiaphragms for their bioactivities. The initial separation of mono- and bis-quaternary ammonium compounds turned out to be very challenging on regular silica gel chromatography. Therefore, a facile purification method, in which the silica gel was pretreated with methanolic sodium bromide solution, was finally achieved. Compounds 3g (0.36 μm) and 4g (0.37 μm) exhibited excellent neuromuscular blocking activities, which were about sixfold to sevenfold higher in potency than that of rocuronium (2.50 μm). In addition, other bis-quaternized compounds also showed good potencies close to that of rocuronium. Furthermore, the preliminary structure-activity relationship of this series was also elucidated. Benzyl group was found to be a promising quaternary group in this series.

In Vitro Evaluation of the Biocompatibility of Newly Synthesized Bis-Quaternary Ammonium Compounds with Spacer Structures Derived from Pentaerythritol or Hydroquinone.

With the object of developing new biocides milder for human use than the current antiseptics, we synthesized a series of bis-quaternary ammonium compounds (bis-QACs). The antimicrobial activity of the newly synthesized bis-QACs and common biocides used as antiseptics was compared by examining minimum inhibitory concentrations and minimum bactericidal concentrations (MBCs). Moreover, the cytotoxicity of these compounds against human cells was determined to calculate the biocompatibility index (BI) of these compounds. BI was the ratio of the concentration of a biocide giving a 50% lethal effect on normal human epidermal keratinocytes to its MBC against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The commonly used antiseptics tested were benzalkonium chloride (BAC), octenidine dihydrochloride (OCT), chlorhexidine digluconate (CHG) and polyhexamethylene biguanide (PHMB). In comparison with these antiseptics, it was shown that some of new bis-QACs exhibited a wider and more potent antimicrobial spectrum than OCT. The cytotoxicity of these bis-QACs was equal or lower compared to that of the quaternary ammonium compounds (BAC and OCT), although these bis-QACs showed higher toxicity than the biguanide-based compounds (CHG and PHMB). Finally, the comparison of BIs revealed that new bis-QACs such as N-dodecyl ｛4,4'-(2,4,8,10-tetraoxaspiro［5.5］undecan-3,9-diyl) ｝dipyridinium dibromide (4TOSU-12), 3,3'-［1,4-Phenylenebis (oxy)］bis (1-dodecylpyridinium) dibromide (3PHBO-12) and 3-(3-Hydroxy-2-(hydroxymethyl)-2-｛［(1-dodecylpyridinium-3-yl) oxy］methyl｝propoxy)-1-dodecylpyridinium dibromide (3HHDMP-12) had equal or greater biocompatibility than the commonly used biocides tested. Thus, these results strongly suggested that 4TOSU-12, 3PHBO-12 and 3HHDMP-12 could be useful as antiseptics for topical application to the skin.

Variable Electrospray Ionization and Matrix-Assisted Laser Desorption/ Ionization Mass Spectra of the Bisquaternary Ammonium Salt Ethonium

Determination of a single “fingerprint” mass spectrum of a biologically active compound, required for compound identification in mixtures and biological materials in such applied tasks as ecological monitoring and biological imaging, may become a nontrivial problem for labile compounds whose mass spectra depend strongly on the applied experimental conditions. In the present communication, qualitatively different mass spectral patterns obtained for the bisquaternary ammonium salt ethonium Cat2+•2Cl– under varied conditions of electrospray ionization and matrixassisted laser desorption/ionization (MALDI) are described and systematized. It is shown that qualitative changes in the electrospray mass spectra of ethonium occur upon a cone voltage increase from 10 V to 100 V, which are caused by the subsequent appearance and destruction of several primary ions: the intact dication Cat2+, the dication-counterion cluster Cat2+•Cl– and[Cat ‑ H]+ and [Cat ‑ CH3]+ ions. Novel experimental evidence of survival of the gas-phase dication Cat2+ with the shortest possible distance of ca 4 Co between the quaternary nitrogen atoms provided by two CH2 groups and Cat2+ fragmentation with preservation of the doubly charged state of the fragments are revealed under soft electrospray conditions. The interpretation of the MALDI mass spectrum is made taking into account the formation of a salt of the bisquaternary ammonium base and 2,5-dihydroxybenzoic acid, which results in the absence of any chlorine-containing ions in the mass spectra and a fragment ion distribution that is different from that observed under electrospray ionization conditions. The main mass spectral features revealed for ethonium may aid in the identification of other types of bisquaternary ammonium compounds.

Probing of the combined effect of bisquaternary ammonium antimicrobial agents and acetylsalicylic acid on model phospholipid membranes: differential scanning calorimetry and mass spectrometry studies

A model molecular biosystem of hydrated dipalmitoylphosphatidylcholine (DPPC) bilayers that mimics cell biomembranes is used to probe combined membranotropic effects of drugs by instrumental techniques of molecular biophysics. Differential scanning calorimetry reveals that doping of the DPPC model membrane with individual bisquaternary ammonium compounds (BQAC) decamethoxinum, ethonium, thionium and acetylsalicylic acid (ASA) leads to lowering of the membrane melting temperature (Tm) pointing to membrane fluidization. Combined application of the basic BQAC and acidic ASA causes an opposite effect on Tm (increase), corresponding to the membrane densification. Thus, modulation of the membranotropic effects upon combined use of the drugs studied can be revealed at the level of model membranes. Formation of noncovalent supramolecular complexes of the individual BQACs and ASA with DPPC molecules, which may be involved in the mechanism of the drug-membrane interaction at the molecular level, is demonstrated by electrospray ionization (ESI) mass spectrometry. In the ternary (DPPC + ASA + BQAC) model systems, the stable complexes of the BQAC dication with the ASA anion, which may be responsible for modulation of the membranotropic effects of the drugs, were recorded by ESI mass spectrometry. The proposed approach can be further developed for preliminary evaluation of the combined effects of the drugs at the level of model lipid membranes prior to tests on living organisms.

Model mass spectrometric study of competitive interactions of antimicrobial bisquaternary ammonium drugs and aspirin with membrane phospholipids

Aim. The aim of the study is to reveal molecular mechanisms of possible activity modulation of antimicrobial bisquaternary ammonium compounds (BQAC) and aspirin (ASP) through noncovalent competitive complexation under their combined introduction into the model systems with membrane phospholipids. Methods. Binary and triple systems containing either decamethoxinum or ethonium, or thionium and aspirin, as well as dipalmitoylphosphatidylcholine (DPPC) have been investigated by electrospray ionization mass spectrometry. Results. Basing on the analysis of associates recorded in the mass spectra, the types of nonocovalent complexes formed in the systems studied were determined and the supposed role of the complexation in the BQAC and ASP activity modulation was discussed. The formation of associates of BQAC dications with ASP anion is considered as one of the possible ways of deactivation of ionic forms of the medications. The formation of stable complexes of BQAC with DPPC and ASP with DPPC in binary systems as well as the complexes distribution in triple-components systems BQAC:ASP:DPPC point to the existence of competition between drugs of these two types for the binding to DPPC. Conclusions. The results obtained point to the competitive complexation in the model molecular systems containing the BQAC, aspirin and membrane phospholipids. The observed phenomenon testifies to the possibility of modulating the activity of bisquaternary antimicrobial agents and aspirin under their combined usage, due to the competition between the drugs for binding to the target membrane phospholipid molecules and also due to the formation of stable noncovalent complexes between BQAC and ASP.

ChemInform Abstract: Quaternary Ammonium Salts and Their Antimicrobial Potential: Targets or Nonspecific Interactions?

AbstractReview: 82 refs.

Quaternary Ammonium Salts and Their Antimicrobial Potential: Targets or Nonspecific Interactions?

For more than 50 years dequalinium chloride has been used successfully as an antiseptic drug and disinfectant, particularly for clinical purposes. Given the success of dequalinium chloride, several series of mono- and bisquaternary ammonium compounds have been designed and reported to have improved antimicrobial activity. Furthermore, many of them exhibit high activity against mycobacteria and protozoa, especially against plasmodia. This review discusses the structure-activity relationships and the modes of action of the various series of (bis)quaternary ammonium compounds.

Lyotropic Mesophase of Hydrated Phospholipids as Model Medium for Studies of Antimicrobial Agents Activity

The lyotropic L α-phase of hydrated dipalmitoylphosphatidylcholine has been proposed as a solvent medium for modeling the effects of membranotropic agents upon cell membranes, including interactions between different agents inside the membrane. For quasibinary systems containing bisquaternary ammonium compounds decamethoxinum or aethonium and 2,5-dihydroxybenzoic acid, calorimetry data allowed us to establish the stoichiometry of the intermolecular complexes incorporated in the membrane. The interaction mechanisms have been clarified using additional data obtained with tetramethylammonium and l-menthol, which model the moieties of the decamethoxinum molecule separated by the alkyl chain. Possible implications of the obtained results for pharmacology are discussed.

The antimicrobial activities of a series of bis-quaternary ammonium compounds

Abstract A series of bis-quaternary ammonium compounds (bis-QACs) N, N ′-hexamethylenebis(1-alkyl-4-carbamoyl pyridinium bromide) (4BCAP-6, n ) (alkyl chain length, n = 8, 10, 12, 14, 16 and 18) were synthesized and characterized. Their surface tensions, critical micelle concentrations (CMC), and antimicrobial activities were evaluated. 4BCAP-6, 10 exhibited the strongest antimicrobial activities except for that against Proteus vulgari . The activities of 4BCAP-6, n against Escherichia coli zk126 were not significantly influenced by temperature, pH and initial bacteria concentration. These results indicate that bis-QACs exhibit high antimicrobial activity regardless of the environmental conditions.

Synthesis and neuromuscular blocking activity of 16-(2- and 3-pyridylmethylene) dehydroepiandrosterone derivatives

The interonium distance plays a major role in neuromuscular blocking activity of bis-quaternary ammonium compounds. In this study we tried to alter the distance between two quaternary nitrogens in some of the steroidal derivatives synthesized and evaluated them for neuromuscular blocking activity using in vivo (in chicks) and in vitro models (rectus abdominus and chick biventer cervis muscle) for their mechanism of action. All the synthesized compounds have shown to possess good depolarizing, competitive neuromuscular blocking activity, particularly the 17-acetoxy derivative and the increase in the distance between two quaternary nitrogens decreased the activity.

Bis-Pyridinium cyclophanes: Novel ligands with high affinity for the blood–brain barrier choline transporter

A series of bis-pyridinium cyclophane analogs designed as conformationally restricted bis-quaternary ammonium compounds were evaluated for their affinity for the blood–brain barrier (BBB) choline transporter. All the cyclophanes investigated exhibited high affinity compared to choline. Of these compounds, N, N′-(1,10-decanediyl)3,3′-(1,9-decadiyn-1,10-diyl)- bis-pyridinium diiodide ( 5c) and N, N′-(1,9-nonanediyl)3,3′-(1,9-decadiyn-1,10-diyl)- bis-pyridinium dibromide ( 5b) exhibited highest affinity with K i values of 0.8 μM and 1.4 μM, respectively, and constitute some of the most potent BBB choline transporter ligands reported.

Spacer Effects in Novel Cationic Surfactants as a Primordial Parameter for an Optimal Inhibition of SRB

AbstractFour bisquaternary ammonium surfactants, low toxic compounds capable of inhibiting sulfate‐reducing bacteria (SRB), were synthesized and characterized by spectral studies IR,1H‐NMR and elemental analyses. The growth of the reference SRB (Desulfomonas pigra) was shown to be completely inhibited by bisquaternary ammonium surfactants. Structure–activity relationships are discussed, as well as the critical micelle concentration (cmc), the saturated adsorption amount (Г∞) and the minimum average area per surfactant molecule (Amin). The influence of the hydrophobic chain length, the number of methylene groups, and the influence of that spacer group on the surfactant properties of synthesized bisquaternary ammonium compounds are discussed. The presence of a long hydrophobic alkyl chain was a primordial parameter for optimal biological activity. The number of SRB and their inhibition efficiency were subject to considerable parameters, maximum values being noted in presence of all paper biocides. A direct relationship has found between the number of SRB and Amin.

Exploring Unique Structures: Flexibility is a Significant Factor in Biological Activity

The effect of molecular flexibility on biological activity was described for soft (e.g. hGH peptides) and hard molecules (e.g. biscoclaurine-type alkaloids). These molecules had a macrocyclic structure during molecular mechanics analysis, and the minimum essential unit, which affects insulin-involved fatty acid synthesis, was observed. The flexibility of the molecular center is concerning with biological activity through the diversification of structural feature, and compared with two types of molecules which have a rigid (haloacetylcarbamoyl-2-nitroimidazole analogs: chiral-TXs) or flexible (bis-quaternary ammonium compounds: bis-QACs) molecular center. Center flexibility reflected the conformation occurrence in TXs and bis-QACs. A parameter (solvation-free energy: dGW), which reflects structural hydrophobicity, was shown, and applied to the molecular design of brefeldin A analog. This hydrophobic index was very useful, and was used for conformational analysis of chiral-TXs and bis-QACs. In molecular dynamics analysis of cholesterol-dependent cytolysin (e.g. streptolysin O) and -independent cytolysin (e.g. intermedilysin), whole molecules moved like a bow and different conformations were shown in every moment. In such situations, the membrane-associated 11mer region in these cytolysins were flexible and could always interact with extramolecular factors (e.g. membrane constitution).