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.     

Antibacterial activity of new dibenzoxepinone oximes with fluorine and trifluoromethyl group substituents

In this paper we present the antimicrobial activity of some newly synthesized dibenz[b,e]oxepin derivatives bearing the oximino moiety, and fluorine (F) and trifluoromethyl (CF(3)) group substituents. The chemical structure and purity of the new compounds were assessed by using elemental analysis, NMR and FTIR spectroscopy. The new compounds were screened for their antibacterial activity towards Gram-positive and Gram-negative strains, by qualitative and quantitative assays. Our results demonstrated that the CF(3) and F disubstituted compounds could be considered for the further development of novel antimicrobial drugs.     

Chemoenzymatic synthesis and antimicrobial and haemolytic activities of amphiphilic bis(phenylacetylarginine) derivatives

Novel bis(N(alpha)-phenylacetyl-L-arginine)-alpha,omega-alkanediamide dihydrochloride (bis(PhAcArg)) derivatives with antimicrobial activity were designed and synthesised by a chemoenzymatic strategy. The new structures consist of two N(alpha)-phenylacetyl-L-arginine moieties connected by an alkanediamine spacer chain of 6, 8, 10, 12, and 14 methylene units through amide bonds. The key step in the chemoenzymatic strategy is the double aminolysis of the N(alpha)-phenylacetyl-L-arginine methyl ester by the corresponding alpha,omega-alkanediamine catalyzed by papain in ethanolic media. The compounds synthesised were tested as antimicrobials against 15 bacterial and 8 fungal species. The antimicrobial activity and selectivity depend strongly on the spacer chain length. The bis(PhAcArg) derivative with the spacer chain of 12 methylene groups gave the lowest MIC values against Gram-positive bacteria, whereas that with 14 methylene units was the best against Gram-negative bacteria. Interestingly, these novel compounds showed enhanced antibacterial activity relative to the lead compound, bis(N(alpha)-caproyl-L-arginine)-1,3-propanediamide dihydrochloride (C(3)(CA)(2)), and moderate antifungal activity. Moreover, tests of haemolytic activity toward human erythrocytes revealed that haemolysis increases with spacer chain length. Importantly, the compounds were classified as not irritating to eyes, with the exception of the compound with the spacer chain of 14 methylene groups, which was a slight eye irritant.     

Design and Synthesis of Menthol and Thymol Derived Ciprofloxacin: Influence of Structural Modifications on the Antibacterial Activity and Anticancer Properties

Sixteen new Ciprofloxacin derivatives were designed and successfully synthesized. In an in silico experiment, lipophilicity was established for obtained compounds. All compounds were screened for antimicrobial activity using standard and clinical strains. As for Gram-positive hospital microorganisms, all tested derivatives were active. Measured MICs were in the range 1–16 µg/mL, confirming high antimicrobial potency. Derivative 12 demonstrated activity against all standard Gram-positive Staphylococci, within the range of 0.8–1.6 µg/mL and was confirmed as the leading structure with MICs 1 µg/mL for S. pasteuri KR 4358 and S. aureus T 5591 (clinical strains). All compounds were screened for their in vitro cytotoxic properties via the MTT method. Three of the examined compounds (3, 11 and 16) showed good activity against cancer cells, and in parallel were found not to be cytotoxic toward normal cells. Doxorubicin SI ranged 0.14–1.11 while the mentioned three ranged 1.9–3.4. Selected Ciprofloxacin derivatives were docked into the crystal structure of topoisomerase II (DNA gyrase) in complex with DNA (PDB ID: 5BTC). In summary, leading structures were established (3, 11, 12 and 16). We have observed poor results in preformed studies for disubstituted derivatives, suggesting that 3-oxo-4-carboxylic acid core is the active DNA-gyrase binding site, and when structural changes were made in this fragment, there was an observed decrease in antibacterial potency.     

Polymeric phosphonium salts as a novel class of cationic biocides. VII. Synthesis and antibacterial activity of polymeric phosphonium salts and their model compounds containing long alkyl chains

Various polymeric phosphonium salts containing long alkyl chains (C₁₀? C₁₈) and their corresponding model compounds were prepared, which possess the same hydrophobic structure as that of the common disinfectants (quaternary ammonium salts), and their antibacterial activities were evaluated by means of the viable cell counting method against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). The polymer with the decyl group exhibited a higher activity than that of the corresponding model compound, particularly against the Gram-positive strain. Furthermore, antibacterial activity of the polymers was found to decrease as the chain length increased. In contrast with the polymers, the antibacterial activity of the corresponding model compounds increased as hydrophobicity of the substituents increased. The antibacterial activity was strongly dependent on the structure, particularly on the length of the alkyl chain. © 1994 John Wiley & Sons, Inc.     

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.     

Solid-phase synthesis, characterization, and antibacterial activities of metallocene-peptide bioconjugates

This work shows how the introduction of an organometallic group enhances and modifies the specificity of biologically active peptides. Ferrocene was chosen as an organometallic group because it has been shown to alter the pharmacodynamic profile of bioactive compounds. A comparison with the isosteric cobaltocenium group allows one to explore the influence of charge and redox potential on the biological activity of the conjugates. Arginine and tryptophan containing peptides H-WRWRWR-NH(2) and H-RWRWRW-NH(2) and the metallocene peptide bioconjugates [M]-C(O)-RWRWR-NH(2) and [M]-C(O)-WRWRW-NH(2), where [M]=[Co(Cp)(C(5)H(4))](+), [Fe(Cp)(C(5)H(4))] were prepared by solid-phase peptide synthesis (SPPS). They were purified by HPLC, characterized by ESIMS and NMR spectroscopy, and tested for antibacterial properties against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus using the minimum inhibitory concentration (MIC) test. In most cases, no metal-specific activity could be observed. However, the conjugate [Fe(Cp)(C(5)H(4))-C(O)-WRWRW-NH(2)] 6 was found to be particularly effective against the Gram-positive S. aureus. The activity of this metallocene-pentapeptide conjugate (7.1 microM) was even better than the 20 amino acid naturally occurring pilosulin 2, which was used as a positive control. Unlike all other compounds tested, which were most active against the Gram-negative E. coli strain, the ferrocene conjugate 6 was the only compound in this series that was most active against Gram-positive bacteria. Given the health concerns resulting from multidrug resistant S. aureus strains, the incorporation of metallocenes may provide a novel line of attack.     

Synthesis and Properties of Dicephalic Cationic Surfactants Containing a Quaternary Ammonium and a Guanidine Group

Novel dicephalic surfactants containing a quaternary ammonium and a guanidine group were synthesized, and the effect of the alkyl chain length on micellization and antimicrobial activity were investigated. Surface tension and conductivity were applied to study the self-aggregation of the amphiphilic molecule in aqueous solution. The results indicated that these compounds reduce the surface tension to a level of 30–36 mN/m at the air/water interface and that there is a characteristic chain length dependence of the micellization process of surfactants. The antimicrobial activity was evaluated against Gram-negative, Gram-positive bacteria and fungi, indicating strong antibacterial activity against tested strains.     

Novel (+)-Neoisopulegol-Based O-Benzyl Derivatives as Antimicrobial Agents

Discovery of novel antibacterial agents with new structures, which combat pathogens is an urgent task. In this study, a new library of (+)-neoisopulegol-based O-benzyl derivatives of aminodiols and aminotriols was designed and synthesized, and their antimicrobial activity against different bacterial and fungal strains were evaluated. The results showed that this new series of synthetic O-benzyl compounds exhibit potent antimicrobial activity. Di-O-benzyl derivatives showed high activity against Gram-positive bacteria and fungi, but moderate activity against Gram-negative bacteria. Therefore, these compounds may serve a good basis for antibacterial and antifungal drug discovery. Structure–activity relationships were also studied from the aspects of stereochemistry of the O-benzyl group on cyclohexane ring and the substituent effects on the ring system.     

Semisynthetic Vitamin E Derivatives as Potent Antibacterial Agents against Resistant Gram-Positive Pathogens

New 5-substituted vitamin E derivatives were semisynthesized, and their antibacterial activity against human Gram-positive and Gram-negative pathogens was evaluated. Several vitamin E analogues were active against methicillin-resistant Staphylococcus aureus (MRSA) and/or methicillin-resistant Staphylococcus epidermidis (MRSE); structure-activity relationships (SARs) are discussed. As a result, it is shown that the presence of a carboxylic acid function at the C-5 position and/or at the end of the side chain is crucial for the antibacterial activity. The bactericidal or bacteriostatic action of three compounds against MRSA and MRSE was confirmed in a time-kill kinetics study, and the cytotoxicity on human cells was evaluated. The preliminary mechanism study by confocal microscopy indicated that those vitamin E analogues led to bacterial cell death through membrane disruption.     

Antifeedant and Phytotoxic Activity of the Sesquiterpene <Emphasis Type="Italic">p</Emphasis>-Benzoquinone Perezone and Some of its Derivatives

The sesquiterpene p-benzoquinone perezone (1), isolated from Perezia adnata var. alamani (Asteraceae), and its non-natural derivatives isoperezone (2), dihydroperezone (3), dihydroisoperezone (4), and anilidoperezone (5) were tested as antifeedants against the herbivorous insects Spodoptera littoralis, Leptinotarsa decemlineata, and Myzus persicae. Compounds 1-5 exhibited strong antifeedant activity against L. decemlineata and M. persicae, and elicited a low response by S. littoralis. Antifeedant activity on L. decemlineata and M. persicae increased when the hydroxyl group at C-3 in perezone (1) was changed to C-6 to give isoperezone (2). The same effect was found with hydrogenation of the double bond of the alkyl chain of (1) to yield dihydroperezone (3). In contrast, hydrogenation of this double bond in isoperezone (2) to give dihydroisoperezone (4) led to a reduction in antifeedant activity. Determination of the phytotoxic activity of 1-5 revealed that 3 had a significant inhibition effect on Lactuca sativa radicle length growth.     

The Effect of Conjugation of Ciprofloxacin and Moxifloxacin with Fatty Acids on Their Antibacterial and Anticancer Activity

Novel conjugates (CP) of moxifloxacin (MXF) with fatty acids (1m–16m) were synthesized with good yields utilizing amides chemistry. They exhibit a more pronounced cytotoxic potential than the parent drug. They were the most effective for prostate cancer cells with an IC₅₀ below 5 µM for respective conjugates with sorbic (2m), oleic (4m), 6-heptenoic (10m), linoleic (11m), caprylic (15m), and stearic (16m) acids. All derivatives were evaluated against a panel of standard and clinical bacterial strains, as well as towards mycobacteria. The highest activity towards standard isolates was observed for the acetic acid derivative 14m, followed by conjugates of unsaturated crotonic (1m) and sorbic (2m) acids. The activity of conjugates tested against an expanded panel of clinical coagulase-negative staphylococci showed that the compound (14m) was recognized as a leading structure with an MIC of 0.5 μg/mL denoted for all quinolone-susceptible isolates. In the group of CP derivatives, sorbic (2) and geranic (3) acid amides exhibited the highest bactericidal potential against clinical strains. The M. tuberculosis Spec. 210 strain was the most sensitive to sorbic (2m) conjugate and to conjugates with medium- and long-chain polyunsaturated acids. To establish the mechanism of antibacterial action, selected CP and MXF conjugates were examined in both topoisomerase IV decatenation assay and the DNA gyrase supercoiling assay, followed by suitable molecular docking studies.     

Functionalized Cyclopentenones and an Oxime Ether as Antimicrobial Agents

Several naturally occurring cyclopentenones, such as palmenones and nigrosporiones, exhibit antimicrobial activity. Herein we describe the antimicrobial activity of cyclopentenones and derivatives that can be easily accessed from biomass derivatives furfural and 5-hydroxymethylfurfural. Upon screening a range of functionalized trans-diamino-cyclopentenones (DCPs) and δ-lactone-fused cyclopentenones (LCPs), an oxime ether derivative of DCP was identified that exhibited remarkable antimicrobial activity against Gram-positive bacteria, including resistant strains such as methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE) strains.     

Synthesis,Biological Activity and Molecular Docking Studies of Novel Nicotinic Acid Derivatives

In our research, we used nicotinic acid as a starting compound, which was subjected to a series of condensation reactions with appropriate aldehydes. As a result of these reactions, we were able to obtain a series of twelve acylhydrazones, two of which showed promising activity against Gram-positive bacteria (MIC = 1.95–15.62 µg/mL), especially against Staphylococcus epidermidis ATCC 12228 (MIC = 1.95 µg/mL). Moreover, the activity of compound 13 against the Staphylococcus aureus ATCC 43300 strain, i.e., the MRSA strain, was MIC = 7.81 µg/mL. Then, we subjected the entire series of acylhydrazones to a cyclization reaction in the acetic anhydride, thanks to which we were able to obtain twelve new 3-acetyl-2,5-disubstituted-1,3,4-oxadiazoline derivatives. Obtained 1,3,4-oxadiazolines were also tested for antimicrobial activity. The results showed high activity of compound 25 with a 5-nitrofuran substituent, which was active against all tested strains. The most promising activity of this compound was found against Gram-positive bacteria, in particular against Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538 (MIC = 7.81 µg/mL) and ATCC 43300 MRSA strains (MIC = 15.62 µg/mL). Importantly, the best performing compounds did not show cytotoxicity against normal cell lines. It seems practical to use some of these compounds or their derivatives in the future in the prevention and treatment of infections caused by some pathogenic or opportunistic microorganisms.     

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: III antimicrobial effect of various hexadecyl and quaternary derivatives

Aminimides, a new class of surfactants, have been screened for in vitro antimicrobial activity. Greatest activity against gram (+) and yeast organisms is achieved when a chain length of C₁₆ is reached. This generalization is true whether or not the chain length is joined to the imide or amine group. The type of functional group associated with the surfactant is less important than chain length. Gram (-) organisms do not fit this generalization, since shorter (<C₁₆) rather than longer chain derivatives are more active. The importance of surfactant chain length to biodegrad-ability is discussed.     

Antibiotic and Nematocidal Metabolites from Two Lichen Species Collected on the Island of Lampedusa (Sicily)

The antibiotic and nematocidal activities of extracts from two coastal lichen species collected on Lampedusa Island (Sicily), Ramalina implexa Nyl. and Roccella phycopsis Ach., were tested. Methyl orsellinate, orcinol, (+)-montagnetol, and for the first time 4-chlororcinol were isolated from Roccella phycopsis. (+)-Usnic acid was obtained from Ramalina implexa. The crude organic extract of both lichen species showed strong antibiotic activity against some bacterial species and nematocidal activity. Among all the pure metabolites tested against the infective juveniles (J2) of the root-knot nematode (RKN) Meloydogine incognita, (+)-usnic acid, orcinol, and (+)-montagnetol had significant nematocidal activity, comparable with that of the commercial nematocide Velum^® Prime, and thus they showed potential application in agriculture as a biopesticide. On the contrary, methyl orsellinate and 4-chlororcinol had no nematocidal effect. These results suggest that the substituent pattern at ortho-para-position in respect to both hydroxyl groups of resorcine moiety, which is present in all metabolites, seems very important for nematocidal activity. The organic extracts of both lichens were also tested against some Gram-positive and Gram-negative bacteria. Both extracts were active against Gram-positive species. The extract of Ramalina implexa showed, among Gram-negative species, activity against Escherichia coli and Acinetobacter baumannii, while that from Roccella phycopsis was effective towards all test strains, with the exception of Pseudomonas aeruginosa. The antimicrobial activity of (+)-usnic acid, methyl orsellinate, and (+)-montagnetol is already known, so tests were focused on orcinol and 4-chlororcinol. The former showed antibacterial activity against all Gram positive and Gram-negative test strains, with the exception of A. baumannii and K. pneumoniae, while the latter exhibited a potent antibacterial activity against Gram-positive test strains and among Gram-negative strains, was effective against A. baumannii and K. pneumonia. These results suggest, for orcinol and 4-chlororcinol, an interesting antibiotic potential against both Gram-positive and Gram-negative bacterial strains.     

Antimicrobial Potential of Chiral Amide Derivatives of Ricinoleic and 3-Hydroxynonanoic Acid

The growing role of fatty acid amides in medicinal chemistry has recently been observed. Therefore, using simple and fast methods, a series of chiral amide derivatives (24 compounds) of ricinoleic and 3-hydroxynonanoic acid was obtained with 31–95% yields. Then, the evaluation of their antimicrobial activity against 13 microorganisms representing Gram-positive and Gram-negative bacteria, yeast, and molds was performed. The obtained compounds showed antimold potential; however, the tested species of molds were more susceptible to derivatives of 3-hydroxynonanoic acid than to amides obtained from ricinoleic acid (RA). Interestingly, hydroxamic acids derived from RA exhibited the best activity against Candida albicans and Candida tropicalis. On the other hand, hydroxamic acids derived from 3-hydroxynonanoic acid showed the best antimicrobial potential against the remaining tested microorganisms, especially against Pseudomonas cedrina. The obtained derivatives can be considered compounds of potential pharmacological significance, which is important due to the increasing problem of microbial resistance.     

Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains

Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria‐related deaths, has developed resistance against this drug. Twenty‐seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro‐2H‐quinolizine and 1,2,3,4,5,6‐hexahydro‐1,5‐methano‐8H‐pyrido[1,2‐a][1,5]diazocin‐8‐one, were synthesized and tested for activity against D‐10 (CQ‐susceptible) and W‐2 (CQ‐resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub‐micromolar IC₅₀ values. Eleven compounds were found to be 2.7‐ to 13.4‐fold more potent than CQ against the W‐2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC‐1 and HepG2) along with easier synthetic accessibility. Replacement of the 4‐NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria.