Synthesis and Evaluation of a Series of Bis(pentylpyridinium) Compounds as Antifungal Agents

A series of bis(4‐pentylpyridinium) compounds with a variety of spacers between the pyridinium headgroups was synthesised, and the antifungal activity of these compounds was investigated. Lengthening the alkyl spacer between the pentylpyridinium headgroups from 12 to 16 methylene units resulted in increased antifungal activity against C. neoformans and C. albicans, but also resulted in increased hemolytic activity and cytotoxicity against mammalian cells. However, inclusion of an ortho‐substituted benzene ring in the centre of the alkyl spacer resulted in decreased cytotoxicity and hemolytic activity, while maintaining antifungal potency. Replacement of the alkyl and aromatic‐containing spacers by more hydrophilic ethylene glycol groups resulted in a loss of antifungal activity. Some of the compounds inhibited fungal PLB1 activity, but the low correlation of this inhibition with antifungal potency indicates PLB1 inhibition is unlikely to be the predominant mode of antifungal action of this class of compounds, with preliminary studies suggesting they may act via disruption of fungal mitochondrial function.     

Antimicrobial and Cytotoxic Properties of Bisquaternary Ammonium Bromides of Different Spacer Length

A group of cationic gemini surfactants (bisquaternary ammonium bromides) with different spacer chain lengths (8–6–8, 8–7–8, 8–8–8, 8–9–8) was investigated, paying special attention to antimicrobial and the cytotoxic properties as well as their antimicrobial activity during long‐term storage. It was shown that the compounds investigated exhibit excellent antimicrobial activity against Gram‐positive bacteria (Staphylococcus aureus) and Gram‐negative bacteria (Pseudomonas aeruginosa) as well as antifungal properties (Candida albicans). The gemini surfactants tested had the differential level of cytotoxicity against normal lymphocytes. It was shown that the spacer chain length plays an important role in antibacterial activity and influences the cytotoxicity. The gemini surfactants with shorter spacer chain length, that had higher critical micelle concentration, showed generally weaker antibacterial properties, but on the other hand, these exhibited lower level of cytotoxicity. Furthermore, the aqueous solution of gemini surfactants exhibited the same antimicrobial activity even after 3 months.     

A Detailed Study of Antibacterial 3‐Acyltetramic Acids and 3‐Acylpiperidine‐2,4‐diones

Inspired by the core fragment of antibacterial natural products such as streptolydigin, 3‐acyltetramic acids and 3‐acylpiperidine‐2,4‐diones have been synthesised from the core heterocycle by direct acylation with the substituted carboxylic acids using a strategy which permits ready access to a structurally diverse compound library. The antibacterial activity of these systems has been established against a panel of Gram‐positive and Gram‐negative bacteria, with activity mostly against the former, which in some cases is very potent. Data consistent with modes of action against undecaprenylpyrophosphate synthase (UPPS) and/or RNA polymerase (RNAP) for a small subset of the library has been obtained. The most active compounds have been shown to exhibit binding at known binding sites of streptolydigin and myxopyronin at UPPS and RNAP. These systems offer potential for their antibacterial activity, and further demonstrate the use of natural products as biologically validated starting points for drug discovery.     

Surface-Active Properties and Antimicrobial Study of Conventional Cationic and Synthesized Symmetrical Gemini Surfactants

Symmetrical gemini surfactants of cationic series α,ω-alkanediyl bis (dimethyl ammonium bromide) commonly referred as “m–s–m” have been synthesized. Spectral analysis was performed to confirm compound structures and purity. Conductivity and surface tension measurements provide better understanding of the micellization process. Their self-assembly behavior in aqueous solution is also discussed in detail. The antimicrobial efficacy was measured by bacterial and fungal growth inhibition expressed as minimal inhibitory concentration values against five strains of a representative group of microorganisms viz. Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumonia, Salmonella paratyphi B and Aspergillus niger. All of the synthesized surfactants showed antimicrobial activity against them, but at different levels depending on their structures. The surfactants possessing longer alkyl chains (more hydrophobic environment) demonstrated better antimicrobial functionality. The antimicrobial potency was found to be dependent on the representative target microorganism (Gram-positive bacteria > fungi > Gram-negative bacteria), as well as on the ionic nature of the surfactant (cationic), alkyl chain length (m = 12, 16) and spacer length (s = 2, 4, 6) of the synthesized compounds. Gemini surfactants such as 12-2-12 and 12-4-12 were found to be weakly active whereas 16-2-16 and 16-4-16 compounds proved to be the most potent antimicrobial surface-active agents among the synthesized gemini homologues.     

Synthesis and antimicrobial activities of new water‐soluble bis‐quaternary ammonium methacrylate polymers

New methacrylate monomers containing pendant quaternary ammonium moieties based on 1,4‐diazabicyclo‐[2.2.2]‐octane (DABCO) were synthesized. The DABCO group contains either a butyl or a hexyl pendant group comprising the hydrophobic segment of the monomers and one tether group to the methacrylate moiety. The monomers were homopolymerized in water by using 2,2′‐azobis(2‐methylpropionamide) dihydrochloride (V‐50) as an initiator. The monomers and polymers were characterized by elemental analysis, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), FTIR, and ¹³C‐NMR. The antimicrobial activities of the corresponding small molecules (bis‐quaternary ammonium monocarboxylates) and polymers were investigated against Staphylococcus aureus and Escherichia coli. Although the small molecules did not show any antimicrobial activity, the polymers were moderately effective against both Gram‐positive and Gram‐negative bacteria. The minimum inhibitory concentration (MIC) values of the polymers with butyl and hexyl hydrocarbon chains against S. aureus and E. coli were found to be 250 and 62.5 μg/mL, respectively. The minimum bactericidal concentration (MBC) value for the polymer with the butyl group was higher than 1 mg/mL, whereas the MBC value for the polymer with hexyl group was found to be 62.5 μg/mL. Thus, an increase of the alkyl chain length from 4 to 6 significantly increased the antimicrobial activity of the polymer. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 635–642, 2004     

Evaluation of the Antimicrobial Potential and Toxicity of a Newly Synthesised 4-(4-(Benzylamino)butoxy)-9H-carbazole

One of the greatest threats to human and animal health is posed by infections caused by drug-resistant bacterial strains. Therefore, newly synthesised substances are tested for their antimicrobial activity. Carbazole derivatives seem to be promising antibacterial agents. This study aimed at investigating the toxicity and activity of newly synthesised, functionalised carbazole derivative 2 (4-(4-(benzylamino)butoxy)-9H-carbazole) against various microorganisms. Its antimicrobial potential against Gram-positive and Gram-negative bacteria, yeast, and filamentous fungi was examined according to CLSI (Clinical and Laboratory Standards Institute) standards. The tested compound was found to efficiently inhibit the growth of Gram-positive strains. The addition of carbazole derivative 2 at the concentration of 30 µg/mL caused inhibition of bacterial growth by over 95%. Moreover, about 50 and 45% limitation of Pseudomonas aeruginosa and Aspergillus flavus growth was observed in the samples incubated with the addition of 20 and 60 µg/mL of the compound, respectively. Its addition to the microbial cultures caused an increase in the permeability of the cellular membrane. Slight haemolysis of red blood cells was observed after 24-h treatment with carbazole derivative 2. On the other hand, human fibroblasts were found to be more sensitive to its effects. The activity of the tested compound indicates a possibility of its further modification in order to obtain effective drugs, especially against drug-resistant staphylococci.     

Aminimides: II. Antimicrobial effect of short chain fatty acid derivatives

A new family of surfactants, aminimides, has been screened forin vitro antimicrobial activity. These compounds are active against both bacteria and yeast, activity being a function of chain length. Maximum activity for acetimide and acrylimide amine derivatives was extablished with chain lengths of C₁₄–C₁₆. Homologous compounds with lower or higher chain lengths were less active. While showing low antimicrobial activity against gram negative bacteria, mixtures containing C₁₂ and C₁₆ gave good activity against gram negative strains without losing gram positive activity. Aminimides gave low acute LD₅₀’s (200–400 mg/kg) when tested in mice by intraperitoneal injection.     

Antimicrobial Properties and Cytotoxic Effect of Imidazolium Geminis with Tunable Hydrophobicity

Antimicrobial, membranotropic and cytotoxic properties of dicationic imidazolium surfactants of n-s-n (Im) series with variable length of alkyl group (n = 8, 10, 12, 14, 16) and spacer fragment (s = 2, 3, 4) were explored and compared with monocationic analogues. Their activity against a representative range of Gram-positive and Gram-negative bacteria, and also fungi, is characterized. The relationship between the biological activity and the structural features of these compounds is revealed, with the hydrophobicity emphasized as a key factor. Among dicationic surfactants, decyl derivatives showed highest antimicrobial effect, while for monocationic analogues, the maximum activity is observed in the case of tetradecyl tail. The leading compounds are 2–4 times higher in activity compared to reference antibiotics and prove effective against resistant strains. It has been shown that the antimicrobial effect is not associated with the destruction of the cell membrane, but is due to specific interactions of surfactants and cell components. Importantly, they show strong selectivity for microorganism cells while being of low harm to healthy human cells, with a SI ranging from 30 to 100.     

Synthesis and Biological Evaluation of Papain‐Family Cathepsin L‐Like Cysteine Protease Inhibitors Containing a 1,4‐Benzodiazepine Scaffold as Antiprotozoal Agents

Novel papain‐family cathepsin L‐like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure–activity relationships of these derivatives, with the aim to develop new analogues with a simplified and more synthetically accessible structure and with improved antiparasitic activity. The structure of the model compounds was significantly simplified by modifying or even eliminating the side chain appended at the C3 atom of the benzodiazepine scaffold. In addition, a simple methylene spacer of appropriate length was inserted between the benzodiazepine ring and the 3‐bromoisoxazoline moiety. Several rhodesain and falcipain‐2 inhibitors displaying single‐digit micromolar or sub‐micromolar antiparasitic activity against one or both parasites were identified, with activities that were one order of magnitude more potent than the model compounds.     

Liquid crystalline and photocrosslinkable poly(4,4′‐stilbeneoxy) alkylarylphosphates

Three series of liquid crystalline and photocrosslinkable poly(4,4′‐stilbeneoxy) alkylarylphosphates were synthesized from various 4,4′‐bis(m‐hydroxyalkyloxy)stilbenes (m = 2, 4, 6, 8, 10) and arylphosphorodichloridates in chloroform by solution polycondensation method. Polarized optical microscope (POM) and differential scanning calorimetry (DSC) observations revealed that polymers containing less than four methylene spacer groups did not exhibit liquid crystalline (LC) texture, possibly due to smaller microdomain and restricted movement of the mesogen. In contrast, polymers containing more than four methylene spacer group established LC texture, which has been attributed to the larger monodomain and free movement of mesogens. Thermogravimetric analysis (TGA) data indicated that thermal stability and char yield decreased with increasing flexible methylene spacer groups, increased significantly for biphenyloxy and 1‐naphthyloxy containing polymers than that of phenyloxy containing polymers ascribed to increasing aromaticity, size, and number of aromatic rings. Photocrosslinking of stilbene containing polymers has been shown to proceed via 2π‐2π cycloaddition reaction by Ultra‐violet (UV) and fluorescence. The rate photocrosslinking has been found to increase with increasing number of methylene group in the main chain. The aromaticity of the side chain also increases the rate of crosslinking. POLYM. ENG. SCI., 2012. © 2011 Society of Plastics Engineers     

Motuporamine Derivatives as Antimicrobial Agents and Antibiotic Enhancers against Resistant Gram‐Negative Bacteria

Dihydromotuporamine C and its derivatives were evaluated for their in vitro antimicrobial activities and antibiotic enhancement properties against Gram‐negative bacteria and clinical isolates. The mechanism of action of one of these derivatives, MOTU‐N44, was investigated against Enterobacter aerogenes by using fluorescent dyes to evaluate outer‐membrane depolarization and permeabilization. Its efficiency correlated with inhibition of dye transport, thus suggesting that these molecules inhibit drug transporters by de‐energization of the efflux pump rather than by direct interaction of the molecule with the pump. This suggests that depowering the efflux pump provides another strategy to address antibiotic resistance.     

以金刚烷为联接链的Gemini表面活性剂合成与性能

以1,3-金刚烷二甲酸为起始原料,合成了3种以金刚烷为联接链的具不同疏水链长的Gemini表面活性剂（nP-Ad-Pn,n=12,14,16）。用FTIR、1HNMR、ESI-MS对目标化合物的结构进行了表征。采用表面张力、电导率和稳态荧光光谱测定了金刚烷Gemini表面活性剂的表面活性、胶束化热力学参数和胶束微极性。结果显示：白金环法测得nP-Ad-Pn在25℃下的临界胶束浓度分别为6×10-4、1×10-4和2.5×10-5 mol·L-1,∆G0m和∆H0m均为负值说明表面活性剂胶束形成是一个自发且放热的过程。化合物对金黄色葡萄球菌、枯草杆菌、大肠杆菌、绿脓杆菌、副溶血性弧菌抑菌活性的测定结果表明,12P-Ad-P12对5种菌株的MIC值在0.2～4.2 mg/L,显示出很强的抑菌活性。     

Synthesis and characterization of antimicrobial polylactide via ring‐opening polymerization and click chemistry methods

Novel biodegradable polylactide (PLA) copolymers bearing pendant antimicrobial agent groups were successfully fabricated with a combination of ring‐opening copolymerization and copper(I)‐catalysed azide–alkyne cycloaddition click reaction in a two‐step reaction procedure. First, biodegradable PLA copolymers bearing azido groups were synthesized by the ring‐opening copolymerization of l ‐lactide and 2,2‐ bis(azidomethyl)trimethylene carbonate in the presence of 1‐dodecanol as protic co‐initiator and tin(II) 2‐ethylhexanoate (Sn(Oct)₂) as the catalyst. Then, alkyne functionalized quaternary ammonium salts were attached onto the azido groups of the copolymers via a Huisgen 1,3‐dipolar cycloaddition reaction to give PLA imparting antimicrobial activity. The chemical structure and composition of the copolymers were clearly confirmed using ¹H NMR and Fourier transform infrared spectroscopies and gel permeation chromatography. Thermal phase transition temperatures (T_m and T_g) and the thermal stability of the polymers were investigated by DSC and TGA experiments, respectively. The antimicrobial activity tests were carried out against Gram‐negative (Escherichia coli) and Gram‐positive (Staphylococcus aureus) bacteria by the drop plate method. It was observed that antimicrobial agents are more active in the polymeric form than in the monomeric form. Also, the activity depends on the compositional ratio and the length of the alkyl group on the ammonium salts. © 2018 Society of Chemical Industry     

Synthesis and characterization of liquid crystalline polymers containing aromatic ester mesogen and a nonmesogenic ferrocene unit in the spacer

A new series of liquid crystalline polymers containing aromatic triad ester mesogen and 1,1′‐disubstituted ferrocene as a nonmesogenic unit along with polymethylene spacer was synthesized. The polymer was synthesized by a room temperature polycondensation reaction between bis(4‐chloroformyl phenyloxy alkyl ferrocene dicarboxylate) and quinol. The alkyl groups have been varied by an even number of methylene groups with a range from two to ten groups. All the polymers were found to possess liquid crystalline properties. The identification of the mesophase is more transparent with an increase in the spacer. The thermal characteristics were studied using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The results reveal that the thermal stability of the polymers was decreased with increasing spacer length. The T_g, T_m, and T_i of the polymers decreased with increasing methylene groups. The incorporation of the ferrocene moiety also has a considerable effect on the glass transition temperature. The char yield of the polymer decreases with an increasing methylene chain length. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 3494–3501, 2002     

Aromatic side-chain liquid-crystalline polyurethanes with azobenzene mesogenic units

Summary We have synthesized SC-LCPUs from 1,1'-methylenebis(4-isocyanatobenzene) (MDI) and azobenzene mesogenic diols (α-[bis(2-hydroxyethyl)amino]-ω-(4-R-azobenzene-4'-oxy)alkanes, R = -OCH₃, -CN and -NO₂) with 4, 8 or 12 methylene spacer units. All the C4RMDIP are amorphous polymers showing no mesomorphic properties, whereas for C8RMDIP polyurethanes only C8OMeMDIP is liquid-crystalline. The smectic structures of C12RMDIP polymers are defined by the terminal group; the layer spacing values give the order CN>NO₂>OMe. Received: 10 July 2001 / Revised: 31 January 2002 / Accepted: 14 February 2002     

Synthesis and Modification of Amine-Terminated Maleic Anhydride-Ethylene Copolymers by Benzaldehyde Derivatives: Characterization and Antimicrobial Properties

Antimicrobial polymers based on poly(ethylene-alt-maleic anhydride) (PEMA) were prepared. Amination of poly(ethylene-alt-maleic anhydride) using diamines of different chain lengths such as ethylenediamine (EDA) and hexamethylenediamine (HMDA) afforded terminal amino groups on the polymers. Antimicrobial polymers were obtained by immobilization of benzaldehyde and its derivatives, which include 4-hydroxybenzaldehyde and 2,4-dihydroxybenzaldehyde onto amine-terminated polymers. The antimicrobial activity of the prepared polymers were examined against different types of microorganisms including Gram-positive and Gram-negative bacteria as well as some fungi. The obtained results revealed that the antimicrobial activity increased with increasing the number of phenolic hydroxyl group and with increasing the spacer length.     

Antimicrobial lipids: Natural and synthetic fatty acids and monoglycerides

Over 40 natural or synthetic lipophilic compounds were screened for antimicrobial activity. Gram (+) bacteria and yeasts but not Gram (−) bacteria were affected by these agents. Epimino and selena fatty acids are more active than their corresponding straight chain unsubstituted fatty acids. The position of selenium influenced the antimicrobial activity of the fatty acid. The presence and position of a double or triple bond, usually an important factor in long chain fatty acids (>C₁₄) had little or no effect in C₁₁ fatty acids. Optimum antimicrobial activity was found for fatty acids and their corresponding monoglycerides when the chain length was C₁₂. The dilaurin derivative was not active.     

Novel Ester-linked Anionic Gemini Surfactant: Synthesis,Surface-Active Properties and Antimicrobial Study

A novel anionic gemini surfactant containing an ester bond in the spacer group was synthesized using cardanol as the raw material and characterized by IR, ¹H NMR and ¹³C NMR. The surface properties of the gemini surfactant were investigated and compared with its corresponding single chain surfactant counterpart. It was found that this novel gemini surfactant exhibited a low critical micelle concentration value (1.9 mM) and good efficiency in reducing surface tension of water (33.6 mN/m). The gemini surfactant was found to have antimicrobial activity against Gram-negative (Escherichia coli and Pseudomonas aeruginosa), Gram-positive (Bacillus subtilis and Staphylococcus aureus) bacteria and fungi (Aspergillus niger, Aspergillus flavus, Candida albicans and Rhizopus stolonifer). The gemini as well as the corresponding single chain surfactant showed good antimicrobial activity against all pathogenic microorganisms studied and can be employed as an antimicrobial agent. The synthesized novel anionic gemini surfactant possesses an excellent wettability and low foamability.     

Preparation and evaluation of nonionic amphiphilic phenolic biocides in urethane hydrogels

Phenols are rarely used in the preparation of polyurethanes because of the inherent competitive reaction of the phenolic moiety with isocyanates. This work represents a successful application of the combination of phenols with isocyanates toward the development of phenolic‐based antimicrobial urethane coatings for niche applications. In this effort, a series of nonionic amphiphilic phenolic molecules were prepared by condensation of 4‐hexylresorcinol with the corresponding hydroxyl‐terminated monomethyl poly(ethylene glycol) in the presence of a catalytic amount of acid in refluxing toluene. These new molecules were evaluated against a variety of Gram‐positive and Gram‐negative bacteria for their antimicrobial activity in minimum inhibitory concentration solution testing. The same amphiphilic molecules were also incorporated into a hydrophilic polyurethane hydrogel and dispensed as films for evaluation of surface activity with a newly developed protocol. All samples possessed some degree of surface antimicrobial activity, which was expressed as a log kill reduction in colony‐forming units starting from an initial bacterial concentration of 10⁷ CFU, and structural features of the phenolic compound were found to contribute significantly to the observed antimicrobial activity. The highest activity was observed in samples containing the phenolic compound with the shortest ethylene oxide polar structural feature and therefore highest mobility in the highly polar urethane resin. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Influence of Nature of Spacer and Hydrocarbon Chain Length on Micellar Encapsulation of Polynuclear Aromatic Hydrocarbons by Carbohydrate Derived Non-Ionic Gemini Surfactants in Aqueous Ethanol Medium

Gemini surfactants with rigid aromatic spacer -CH₂-Ar-CH₂-: 6,6′-(N,N′-di(alkyl)-1,4-phenylenedimethylamino)bis(6-deoxy-1,2-O-isopropylidene-α-D-glucofuranose) and Gemini surfactants with flexible aliphatic spacer -(CH₂)₆-: 6,6′-(N,N′-di(2-hydroxyalkyl)-1,6-hexanediamino)bis(6-deoxy-1,2-O-isopropylidene-α-D-glucofuranose) have been synthesized, and their micellar properties for encapsulation of polynuclear aromatic hydrocarbons (PAH) viz. fluorene, anthracene, triptycene, and pyrene in aqueous ethanol medium have been studied by means of electronic spectroscopy. The micellar study reveals that nature of spacer and length of hydrocarbon chain of the surfactant has profound effect on micellar encapsulation of PAH. The surfactants with rigid aromatic spacer show greater encapsulation as compared to surfactants with flexible aliphatic spacer. Moreover, the more hydrophobic surfactant, i.e. the surfactant with a longer hydrocarbon chain, shows greater encapsulation toward PAH which are encapsulated in the order of their smaller size.