RESUMEN
New 1-cetyl-4-aza-1-azoniabicyclo[2.2.2]octane bromide complexes with copper(II) bromide and lanthanum(III) nitrate were characterized using dynamic light scattering and transmission electron microscopy, with self-assembly and the morphological behavior elucidated. For the lanthanum(III) nitrate complex, the 3D crystal structure was characterized using X-ray diffractometry. These metallosurfactants were tested as antitumor agents, and a high cytotoxic effect comparable with doxorubicin was revealed against the M-HeLa and A-549 cell lines. Both complexes were 2 times more active toward the MCF-7 cell line than the breast cancer drug tamoxifen. The cytotoxic mechanism of complexes is assumed to be related to the induction of apoptosis through the mitochondrial pathway.
RESUMEN
Water-soluble trialkylammonium isatin-3-hydrazone derivatives bearing phenolic substituent were easily synthesized with high yields. XRD studies confirmed the presence of these compounds as trans-(Z)-isomers in a crystal. It was shown that an increase in the lipophilicity of the cationic center leads to an increase in activity against Gram-positive bacteria Staphylococcus aureus and Bacillus cereus, including methicillin-resistant Staphylococcus aureus (MRSA) strains. The MIC values of all compounds turned out to be 2-100 times higher than the MIC of norfloxacin against the MRSA strains in the absence of hemo- and cytotoxicity. Antiaggregation and anticoagulation properties were inâ vitro better than for acetylsalicylic acid and sodium heparin drugs. It has been shown by UV spectroscopy and fluorescence microscopy that the mechanism of antimicrobial action of new acylhydrazones is associated with their ability to destroy the bacterial cell membrane.
Asunto(s)
Isatina , Staphylococcus aureus Resistente a Meticilina , Antibacterianos/química , Antibacterianos/farmacología , Hemostasis , Isatina/química , Isatina/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Antimicrobial and cytotoxic activities of several ammonium derivatives of diterpenoids steviol and isosteviol have been investigated in vitro. The results have showed that these compounds possess high antibacterial activity against MRSA strains and cytotoxic effect against cancer cell lines MCF-7, M-HeLa, A-549, PC3, HepG2, T98G. Lead compounds 4 and 5 were detected, which, in the case of the MCF-7 cell line (human breast adenocarcinoma), showed IC50 at the doxorubicin level with a selectivity index of 5.0-5.2. Flow cytometry and laser confocal microscopy analysis demonstrated that the mechanism of cytotoxic effects of the tested compounds on MCF-7 cells could be associated with the induction of apoptosis along the mitochondrial pathway. At the same time, they did not cause hemolysis and showed only slight cytotoxicity with respect to normal human cells of embryonic lung (Wi-38). The obtained results allow us to consider the studied compounds as promising scaffolds for the design of new effective antibacterial drugs and anticancer agents targeting mitochondria.
Asunto(s)
Compuestos de Amonio/farmacología , Antibacterianos/farmacología , Antineoplásicos/farmacología , Diterpenos de Tipo Kaurano/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Compuestos de Amonio/síntesis química , Compuestos de Amonio/química , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diterpenos de Tipo Kaurano/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Structure-activity relationships are important for the design of biocides and sanitizers. During the spread of resistant strains of pathogenic microbes, insights into the correlation between structure and activity become especially significant. The most commonly used biocides are nitrogen-containing compounds; the phosphorus-containing ones have been studied to a lesser extent. In the present study, a broad range of sterically hindered quaternary phosphonium salts (QPSs) based on tri-tert-butylphosphine was tested for their activity against Gram-positive (Staphylococcus aureus, Bacillus cereus, Enterococcus faecalis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria and fungi (Candida albicans, Trichophyton mentagrophytes var. gypseum). The cation structure was confirmed to determine their biological activity. A number of QPSs not only exhibit high activity against both Gram-positive and -negative bacteria but also possess antifungal properties. Additionally, the hemolytic and cytotoxic properties of QPSs were determined using blood and a normal liver cell line, respectively. The results show that tri-tert-butyl(n-dodecyl)phosphonium and tri-tert-butyl(n-tridecyl)phosphonium bromides exhibit both low cytotoxicity against normal human cells and high antimicrobial activity against bacteria, including methicillin-resistant strains S. aureus (MRSA). The mechanism of QPS action on microbes is discussed. Due to their high selectivity for pathogens, sterically hindered QPSs could serve as effective tunable biocides.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacología , Bacterias/efectos de los fármacos , Línea Celular , Hongos/efectos de los fármacos , Humanos , Relación Estructura-ActividadRESUMEN
BACKGROUND: The development of new effective microbicide surfactants and the search for the structure-biological activity relationship is an important and promising problem. Surfactants containing imidazolium fragment attract attention of researchers in the field of chemotherapy, because these compounds often exhibit high antimicrobial activity. The aim of this work is to identify the newly synthesized surfactants from the viewpoint of their potential usefulness in pharmacology and medicine. For this purpose, a detailed study of antimicrobial, hemolytic and cytotoxic activity of dicationic alkylimidazolium surfactants of the m-s-m (Im) series with a variable length of a hydrocarbon tail (m = 10, 12) and a spacer fragment (s = 2, 3, 4) was carried out. METHODS: Aggregation of surfactants in solutions was estimated by tensiometry and conductivity. Antimicrobial activity was determined by the serial dilution technique. Cytotoxic effects of the test compounds on human cancer and normal cells were estimated by means of the multifunctional Cytell Cell Imaging system. Cell Apoptosis Analysis was made by flow cytometry. RESULTS: The test compounds show high antimicrobial activity against a wide range of test microorganisms and do not possess high hemolytic activity. Importantly, some of them display a bactericidal activity comparable to ciprofloxacin fluoroquinolone antibiotic against Gram-positive bacteria, including methicillin-resistant strains of S. aureus (MRSA). The cytotoxicity of the compounds against normal and tumor human cell lines has been tested as well, with cytotoxic effect and selectivity strongly controlled by structural factor and kind of cell line. Superior results were revealed for compound 10-4-10 (Im) in the case of HuTu 80 cell line (duodenal adenocarcinoma), for which IC50 value at the level of doxorubicin and a markedly higher selectivity index (SI 7.5) were demonstrated. Flow cytometry assay shows apoptosis-inducing effect of this compound on HuTu 80 cells, through significant changes in the potential of mitochondrial membrane. MAJOR CONCLUSIONS: Antibacterial properties are shown to be controlled by alkyl chain length, with the highest activity demonstrated by surfactants with decyl tail, with the length of the spacer fragment showing practically no effect. The results indicate that the mechanism of cytotoxic effect of the compounds can be associated with the induction of apoptosis via the mitochondrial pathway. GENERAL SIGNIFICANCE: Selectivity against pathogenic microorganisms and low toxicity against eukaryotic cells allow considering dicationic imidazolium surfactants as new effective antimicrobial agents. At the same time, high selectivity against some cancer cell lines indicates the prospect of their using as components of new anticancer drugs.
Asunto(s)
Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Imidazoles/farmacología , Tensoactivos/farmacología , Antiinfecciosos/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Línea Celular , Línea Celular Tumoral , Hongos/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Imidazoles/química , Pruebas de Sensibilidad Microbiana , Micosis/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Relación Estructura-Actividad , Tensoactivos/químicaRESUMEN
The increase in the resistance of pathogens, in particular Staphylococcus aureus, to the action of antibiotics necessitates the search for new readily available and non-toxic drugs. In solving this problem, phenolic acylhydrazones have high potential. In this communication, the synthesis of quaternary ammonium compounds containing a differently substituted phenolic moiety has been performed. An initial study of antimicrobial activity showed that these compounds are highly selective against S. aureus and B. cereus. The highest activity (MIC 2.0â µm) was shown by hydrazones containing a catechol fragment. These compounds are more than 3-fold more active against S. aureus and 3-10-fold more active against B. cereus than norfloxacin. Low hemolytic and high antioxidant activities of all new compounds were also established.
Asunto(s)
Antibacterianos/farmacología , Antioxidantes/farmacología , Bacillus cereus/efectos de los fármacos , Fenoles/farmacología , Compuestos de Amonio Cuaternario/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Antioxidantes/síntesis química , Antioxidantes/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Fenoles/química , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/químicaRESUMEN
A high-yield synthesis of some novel isatin-3-acylhydrazones on the base of 5-ethylisatin derivatives and Girard's reagent T is described. Antimicrobial activity preliminary SAR study of both 1-benzylated isatins and water-soluble hydrazones was established. The most active against Staphylococcus aureus and Bacillus cereus are ammonium salts bearing 3,4-dichloro- or 4-CF3 substituents in benzyl fragment.
Asunto(s)
Antibacterianos/farmacología , Bacillus cereus/efectos de los fármacos , Hidrazonas/farmacología , Isatina/farmacología , Staphylococcus aureus/efectos de los fármacos , Agua/química , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Hidrazonas/síntesis química , Hidrazonas/química , Isatina/síntesis química , Isatina/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Solubilidad , Relación Estructura-ActividadRESUMEN
Reactions of pyrimidinophanes with two 6-methylthiocytosine and one 5(6)-alkyluracil moieties bridged with each other by polymethylene spacers with methyl or nonyl p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonate and trifluorosulfonate afforded amphiphilic macrocyclic bis-p-toluene-, methane- and trifluorosulfonates. Despite the presence of several reaction centers in the initial pyrimidinophane molecules, protonation and methylation occurred only at the N(1) atom (with quaternization) of the 6-methylthiocytosine moieties. The bacteriostatic and fungistatic activity of the products was estimated. Macrocyclic tosylates exhibit a remarkable selectivity towards Staphylococcus aureus, with MIC values comparable with a reference drug. Bacteriostatic activity of the amphiphilic pyrimidinophanes depends on the size of the macrocycles, and the highest activity corresponds to definite lengths of polymethylene bridges. Besides, the antimicrobial activity of the screened pyrimidine derivatives depends on their topology. While macrocyclic tosylates are more active against bacteria than against fungi, acyclic tosylate with the same structural fragments shows a dramatical decrease of MIC towards mold and yeast with respect to the corresponding macrocycle. It is found that macrocyclic and acyclic tosylates in high dilutions decrease the extracellular lipase activity.