Studies on fungicidal activity of N-phenylcarbamates. IV. Determination of the hydrophobicity of N-phenylcarbamates by high-performance liquid chromatography.
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Carbamates↗
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In vitro antigiardial activity of IRE-6A and IRE-7B, two ethyl-phenylcarbamate derivatives.
Resistance is a practical problem associated to the use of benzimidazoles in the antigiardial therapy. Since benzimidazole-resistant strains of fungi have shown increased sensitivity to phenylcarbamates, in this study we synthesized and in vitro tested novel substituted phenylcarbamates against the protozoa Giardia intestinalis. IRE-6A and IRE-7B, two 4-R-ethyl-phenylcarbamates demonstrated an important antigiardial activity although that was modest when compared to albendazole in axenic cultures of Giardia intestinalis. Results of this study suggest a potential role of phenylcarbamates as alternative to benzimidazoles in the therapy of giardiasis.
Albendazole↗
Selectivity of biohydroxylation with Beauveria bassiana of trans-2-fluorocycloalkyl N-phenylcarbamates.
Biohydroxylation with Beauveria bassiana of racemates and the pure enantiomers of trans-2-fluorocyclohexyl- 3 and trans-2-fluorocycloheptyl N-phenylcarbamates 6 were investigated and compared with results found for the corresponding nonfluorinated parent compounds. In all cases, mixtures of diastereomeric products hydroxylated in the 4-position were isolated, besides products of p-hydroxylation of the aromatic ring and succeeding compounds derived from these primary reaction products. The regioselectivity of hydroxylation by this fungus is not changed by a single fluorine substituent attached closely to the electron-rich anchoring group in the trans-2-position. There is a different influence on the diastereoselectivity of hydroxylation depending on the absolute configuration of the fluorinated substrates. While the transformation of the (S,S)-2-fluorocycloalkyl N-phenylcarbamates is not diastereoselective giving almost 1:1 mixtures of cis- and trans-4-hydroxyl compounds, the corresponding reactions of the (R,R)-isomers led preferentially to the products trans-hydroxylated in the 4-position. The transformation of the racemic fluorinated six-membered N-phenylcarbamate 3 led to products having a very small enantiomeric excess. The fluorine substituent slightly increased the enantioselectivity of transformation of the racemic seven-membered substrate 6 compared to the C(s)()-symmetric nonfluorinated carbamate. Thus, the fluorine substituent in the trans-2-position in these examples did not change the regioselectivity but rather influenced the stereochemistry of biotransformation, depending on the absolute configuration of the substrate and ring size.
Biotransformation↗
High-performance liquid chromatographic enantioseparations on capillary columns containing crosslinked polysaccharide phenylcarbamate derivatives attached to monolithic silica.
Monolithic capillary columns containing native silica gel were covalently modified with 3,5-disubstituted phenylcarbamate derivatives of cellulose and amylose and applied for enantioseparations in capillary LC. The method previously used for covalent immobilization of polysaccharide phenylcarbamate derivatives onto the surface of microparticulate silica gel was successfully adapted for in situ modification of monolithic fused-silica capillary columns. The effects of the nature of polysaccharide and the substituents, as well as of multiple covalent immobilization of polysaccharide derivative on chromatographic performance of capillary columns were studied. The capillary columns obtained using this technique are stable in all solvents commonly used in LC and exhibit promising enantiomer resolving ability.
Amylose↗
Fungal beta-tubulin, expressed as a fusion protein, binds benzimidazole and phenylcarbamate fungicides.
Benzimidazoles are important antitubulin agents used in veterinary medicine and plant disease control. Resistance is a practical problem correlated with single amino acid changes in beta-tubulin and is often linked to greater sensitivity to phenylcarbamates. This negative cross-resistance creates opportunities for durable antiresistance strategies. Attempts to understand the molecular basis of benzimidazole resistance have been hampered by the inability to purify tubulin from filamentous fungi. We have overcome some of these problems by expressing beta-tubulin as a fusion with a maltose binding protein. This fusion protein is soluble, and we confirm for the first time using a gel filtration assay that benzimidazoles indeed bind to beta-tubulin. This binding is reduced by the mutation Glu198-->Gly198, which also confers resistance. Binding of phenylcarbamates is the complete opposite, reflecting their biological activity and the negative cross-resistance. This suggests that the fungicide binding sites fold correctly in the fusion protein.
Base Sequence↗
Permeability profiles of M-alkoxysubstituted pyrrolidinoethylesters of phenylcarbamic acid across caco-2 monolayers and human skin.
PURPOSE: The purpose of the present research was to study 10 m-alkoxysubstituted pyrrolidinoethylesters of phenylcarbamic acid-potential local anesthetics. The relationships between the structure of the molecule, its physicochemical parameters (log D(oct), log k, R(M), solubility) were correlated to the permeability data obtained from permeation experiments in Caco-2 monolayers and excised human skin in vitro. METHODS: The extent and mechanism(s) of permeability of the series were studied through a Caco-2 monolayer in the apical-to-basolateral (a-b) and basolateral-to-apical (b-a) directions. The MTT test was performed to determine cellular damage. In vitro transdermal permeability data were obtained from permeation experiments on excised human skin by using side-by-side chambers. Passive diffusion and iontophoretically enhanced permeability were measured. RESULTS: In Caco-2 monolayers, similar results in the shape of the permeability curves were obtained for the two directions. In the b-a direction, the values of P(app) were approximately 2-6 times greater than in the a-b direction. A plot of drug permeability vs. the number of carbons in the alkoxychain plateaued first, after which the permeability decreased by the increasing lipophilicity of the drug. If the log D(oct) of the ester was > or = 3.4 and the MW > 385 Da, no measurable Caco-2 permeability was found. Cell damage was also higher by the more lipophilic compounds. In excised human skin, the relationship between the passive diffusion of the drugs and the number of carbons in the alkoxychain was parabolic (r2 = 0.95). Introducing low-level electrical current (iontophoresis), transdermal permeability of the more hydrophilic phenylcarbamic acid esters increased clearly. CONCLUSIONS: Lipophilicity and solubility of a compound have crucial roles in the permeation process. A very high lipophilicity has, however, a negative influence on the permeability, both intestinally and transdermally. Iontophoresis significantly increases the diffusion of small and less lipophilic compounds.
Administration, Cutaneous↗
[Analysis of reproductive development of mutant Nicotiana sylvestris plants resistant to isopropyl-N-phenylcarbamate].
An analysis of Nicotiana sylvestris mutant plants resistant to isopropyl-N-phenylcarbamate (IPC), one of the representative from phenylcarbamate herbicides, was carried out. The plants were characterized by pollen semi-sterility caused by disruptions during microsporogenesis and cytoplasm synthesis in microspores. Low seed productivity of mutant plans was caused by the high pollen sterility and partially by the low vital activity of seed-buds. Obtained data testify that mutations inducing IPC-resistance lead to cytogenetical and morphological abnormalities in male generative system development, that results in decreasing of seed productivity in N. sylvestris mutants. Character of discovered cytological disruptions testifies about possible defects in organization and functioning of microtubules in mutant plants that can correlate with mutation(s) in one or several microtubule protein genes.
Carbamates↗
[Local anesthetics. CX. Preparation, activity and partition coefficients of pyrrolidinoethylesters of 2-, 3- and 4-alkoxy-substituted phenylcarbamic acids].
By pyrrolidinoethylalcohol addition on 2-, 3- and 4-alkoxy-substituted phenylisocyanate in non-aqueous toluene medium a series of 30 compounds of the type Pyrrolidinoethylesters of 2-, 3- and 4-alkoxy substituted phenylcarmabim acids were prepared. Pharmacological evaluation results shown after comparing with cocaine and procaine standards that these compounds have a higher index of effectiveness in both types of local anaesthesia. The maximum effectiveness of surface anaesthesia shows Pyrrolidinoethylester of 2-octyloxy phenylcarbamic acid which is 204-times more effective as cocaine. The maximum effectiveness of infiltration anaesthesis shows Pyrrolidinoethylester of 2-heptyloxy phenylcarbamic acid which is 66-times more effective as procaine. Prepared compounds are more effective in the case of surface anaesthesia as in the case of infiltration anaesthesia and they have comparatively high values of partition coefficients P' and P' cal. Comparison of prepared compounds effectiveness and analogic piperidinoethylesters shows that in more cases they are either equal or nearer effective. The values of their P' and P' cal correlate with these results.
Anesthetics, Local↗
Inhibition of bud initiation by ethyl N-phenylcarbamate results in meiotic development in the yeast Saccharomyces cerevisiae.
When diploid cells of Saccharomyces cerevisiae were incubated in acetate growth media containing 2.5 mM ethyl N-phenylcarbamate (EPC), bud initiation was inhibited preferentially, and eventually overgrown, unbudded cells accumulated. During subsequent incubation, meiosis and ascospore formation occurred at high frequencies. The behavior of EPC-treated cells was essentially the same as that of cells transferred to a starvation sporulation medium. EPC thus has a pronounced effect on the mitotic growth of yeast cells, which leads to meiotic development. Our observations indicate that EPC has a decisive function in the initiation of meiosis in rich growth media.
Ammonia↗
Selective inhibition of transition from sexual agglutination to zygote formation by ethyl N-phenylcarbamate in Saccharomyces cerevisiae.
Effects of ethyl N-phenylcarbamate (EPC) on the mating reaction of Saccharomyces cerevisiae were studied, with special attention on the effect on the alpha pheromone action. EPC inhibited zygote formation at a concentration which promoted induction of sexual agglutinability. EPC enhanced agglutinability induction by alpha pheromone, but inhibited alpha-pheromone-induced formation of large pearshaped cells in a mating type. The enhancement of agglutinability induction was accompanied with increased production of a agglutination substance and inhibition of alpha pheromone inactivation. EPC arrested the cell cycle of a cells probably in the step controlled by CDC19, CDC35, cAMP etc., just before the step controlled by CDC28, alpha pheromone etc.
Agglutination↗
QSAR study of antimycobacterial activity of quaternary ammonium salts of piperidinylethyl esters of alkoxysubstituted phenylcarbamic acids.
A series of 17 halogenides of quaternary ammonium salts of the alkylpiperidinylethyl esters of 2-pentoxy (and 2-heptoxy) substituted phenylcarbamic acids were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, and M. avium. Correlation of this action with lipophilicity (log P, 1-octanol-water system) was used for the description of the structure-antimycobacterial activity relationships (QSARs). The activity increased with the increasing lipophilicity of the compounds.
Anti-Bacterial Agents↗
Na+-coupled D-glucose uptake and membrane order of enterocyte brush border membrane vesicles, under the effect of a series of N-phenylcarbamates.
The importance of the hydrophobic effect of exogenous substances and of modifications of membrane order on D-glucose uptake are still poorly defined. Our results show that the concentrative Na+ -coupled D-glucose uptake of rat enterocyte brush border membrane vesicles is inhibited by N-phenylcarbamates increase the membrane order. However, since the concentrations required for membrane order increase are much greater than those active on D-glucose uptake, the effects on lipid order cannot be responsible for the inhibition of D-glucose uptake. Measurements of D-glucose uptake under conditions of Na+ equilibrium show that these carbamates do not act directly on the carrier but indirectly by favouring the dissipation of the Na+ gradient.
Animals↗
Synthesis and evaluation of phenylcarbamate derivatives as ligands for nicotinic acetylcholine receptors.
Phenylcarbamate derivatives were synthesized and evaluated in radioligand binding assays for different nicotinic acetylcholine receptor (nAChR) subtypes. Carbamate derivatives bearing a pyrrolidine or piperidine moiety 8-20 exhibited much lower affinity for alpha7* nAChR than the analogues in the quinuclidine series 21-25, although the same structural elements are present. Furthermore, in contrast to the quinuclidine analogues 21-25, all (S)-pyrrolidine derivatives 8-12 and the piperidine analogues 15 and 16 exhibited higher affinities for alpha4beta2* nAChR.
Animals↗
Synthesis and cholinesterase activity of phenylcarbamates related to Rivastigmine, a therapeutic agent for Alzheimer's disease.
In order to develop new cholinesterase agents effective against Alzheimer's disease (AD) we synthesized some phenylcarbamates structurally related to Rivastigmine and evaluated their in vitro and in vivo biological activity. Among the compounds which displayed the most significant in vitro activity, 1-[1-(3-dimethylcarbamoyloxyphenyl)ethyl]piperidine (31b), in addition to a simple and cheaper synthesis, showed lower toxicity and very similar therapeutic index in comparison with Rivastigmine.
Acetylcholinesterase↗
The effect of taxol and ethyl-N-phenylcarbamate (EPC) on growth and gravitropism in Zea mays L.
The effect of taxol and ethyl-N-phenylcarbamate (EPC) on the growth and gravitropism of maize roots and coleoptiles was studied. Taxol is known to promote the assembly of microtubules (MTs) and stabilizes MTs by preventing depolymerization. EPC, on the contrary, is an anti-microtubule drug that promotes disassembly of MTs. Taxol, at 1 micromole, inhibited gravitropic response of maize roots to about 40%, but did not inhibit growth; at 10 micromoles, it inhibited the gravitropic response of coleoptile segments of maize by approximately 50%, but did not inhibit growth, while 0.5 mM EPC inhibited both the gravitropic response and growth of maize roots by approximately 50%. Taxol, which inhibited the gravitropic response of maize roots and coleoptile segments, had no effect on either the polar or the bilateral transport of auxin. These results indicated that MT polymerization could not occur normally with taxol or EPC, so that if there was any abnormal rearrangement of MT, the gravitropic response was inhibited, which resulted from the inhibition of neither growth nor auxin transport. These results suggested that gravitropic response was related to the MT arrangement, and that both straight growth and the differential growth in gravitropic response could be regulated by different mechanisms.
Antineoplastic Agents, Phytogenic↗
[Acute toxicity of two phenylcarbamates: propham and chloropropham].
The bibliographic data dealing with the acute toxicity of two phenylcarbamates, propham and chloropropham, are not very precise an often contradictory. This work is a restatement and also a demonstration of the high sensitivity of the aquatic animals that we have tested (Amphibia and Crustacea) in comparison with the Mammals (rat and mouse).
Animals↗
Effects of cold and of isopropyl-N-phenylcarbamate on the second meiotic spindle of mouse oocytes.
The meiotic spindle of ovulated mouse oocytes are cold sensitive similar to the mitotic spindles of somatic cells and unicellular organisms. On crushed ice, the spindle microtubules were disorganized between 15 and 60 min of treatment: continuous microtubules depolymerized at first, then kinetochore fibers followed. MTOCs also dispersed during the cold treatment while kinetochores remained intact. The effects of isopropyl-N-phenylcarbamate (IPC) on the reorganization of the meiotic spindle of mouse oocytes were studied after cold disorganization. This drug is an antimitotic agent which appears to act on cells lacking centrioles (higher plants, amoeba, alga) as oocytes do. In ovulated mouse oocytes, IPC disturbed microtubule orientation and the relative distance between MTOCs and chromosomes. However this herbicide did not seem to act on polymerized microtubules and its action was apparently reversible. The disturbances in microtubule orientation are probably due to the displacement of chromosomes and MTOCs, which are loci of microtubule polymerization.
Animals↗
The influence of glycerol, propylene glycol and sorbitol on surface tension, partition coefficient and diffusion of pyrrolidinoethylester of 3-heptyloxy phenylcarbamic acid (drug XX Z).
The influence of glycerol, propylene glycol and sorbitol on surface tension, partition coefficient and diffusion of pyrrolidinoethylester of 3-heptyloxy phenylcarbamic acid (Drug XX Z) from solutions has been studied. It was found that each of the three mentioned auxiliary substances causes, proportionally to its concentration (5, 10, 15 and 20%), the increase of the surface tension and the decrease of the partition coefficient. A correlation between the surface tension and partition coefficient was proved. The diffusion of the drug XX Z was increased due to use of the auxiliary substances. With respect to these results and in accordance with the rules for development of the drug form, sorbitol in concentration 5-10% seems to be an optimal auxiliary substance.
Anesthetics, Local↗