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PubMed1979

Mutagenicity of N-nitroso pyridinol carbamate with the Salmonella/mammalian microsome test.

Pyridinol carbamate was nitrosated to the N,N1-dinitroso derivative and the structure was proved by spectroscopic methods, including chemical ionization mass spectroscopy. By the Ames test, the dinitroso derivative showed a significant dose-dependent mutagenic response with Salmonella typhimurium strains TA 1535 and TA 100; the response became more pronounced in the presence of microsomes. As the dosage of N-nitroso pyridinol carbamate increased, the number of revertant colonies also increased. Pyridinol carbamate was not mutagenic.

Animals↗
PubMed1989

Organophosphorus and carbamate insecticide poisoning in large animals.

Organophosphorus and carbamate insecticides are used commonly in agriculture to control pests of crops and animals. These compounds are toxic and livestock poisoning has occurred from mistaken addition of unused insecticide to feeds and animal access to improperly disposed of materials or "empty" containers. The morbidity rate approximates a third of animals exposed and about half of those affected die. Organophosphorus and carbamate insecticides generate their toxic effects by bonding to and inhibiting ChE enzymes (most importantly, AChE), which are responsible for breaking down the neurotransmitter ACh. The accumulation of ACh results in uninhibited impulse transmission at the cholinergic endings, including autonomic preganglionic junctions, certain neurons in the central nervous system, and motor nerves to the skeletal muscles. This eventually leads to fatigue of end organs; death usually is a result of respiratory failure. The "delayed neuropathy syndrome" is caused by some OP insecticides, but the pathophysiology of this syndrome does not involve the inhibition of ChE and accumulation of neurotransmitter. Over 100 anticholinesterase insecticides are in use. Variations in toxicity exist among these compounds, but larger diversities exist in the likelihood of poisoning because of differences in formulations, solvents, and conditions of use. Young animals usually are more sensitive than adults. Some of these agents are among the most toxic of manmade chemicals. These insecticides generally do not accumulate in tissues. The "chronic" effects depend on accrued physiological changes from frequent exposure to nonlethal doses. Clinical signs occur within minutes to a few hours and include the muscarinic signs of salivation, excessive lacrimation, frequent urination, and diarrhea. Concurrent nicotinic effects include muscular tremors followed by weakness and paralysis. Topical exposure results in similar poisoning but the onset of clinical signs may be delayed. Certain pour-on insecticides may cause a delayed (more than a week) syndrome in some breeds. Diagnosis of OP or carbamate insecticide poisoning is made by (1) interpretation of clinical signs and history that are consistent with this poisoning, (2) detection of the chemical compound in stomach or rumen contents and tissues, and (3) demonstration of the adverse biological effect, ChE inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

(Partial) agonist/antagonist properties of novel diarylalkyl carbamates on histamine H3 receptors.

In the search for new ligands of the histamine H3 receptor, novel diarylalkyl carbamates (1-19) were synthesized as derivatives of 3-(1H-imidazol-4-yl)propanol and -ethanol. Carbamates were built up via isocyanates either from corresponding amines by reaction with diphosgene or from related carboxylic acid/diphenylphosphoryl azide and the alcoholic component. Sterically hindered amines were prepared in a two-step reaction sequence from corresponding ketones. Some of the title compounds showed (partial) agonist activity at the histamine H3 receptor in vitro and in vivo. Diphenylmethyl carbamate 2 was identified as a new lead structure (ED50 = 5.3 +/- 2.6 mg/kg po, alpha = 1.0). Aromatic substitution in ortho- or para-positions of 2 led to a loss of agonist activity. meta-Substitution was tolerated to some extent. These effects seemed to be caused by steric rather than electronic properties of the substituents. An investigation of exchange of one or both phenyl rings of 2 by heterocyclic rings led to the highly active and selective thienyl derivative 18 (ED50 3.4 +/- 1.4 mg/kg p.o., alpha = 1.0). These new (partial) agonists of the histamine H3 receptor might serve as pharmacological tools for investigating molecular aspects of the H3 receptor or as possible centrally acting therapeutic agents with oral bioavailability.

Animals↗
PubMed1999

Molecular recognition by acetylcholinesterase at the peripheral anionic site: structure-activity relationships for inhibitions by aryl carbamates.

Substituted phenyl-N-butyl carbamates (1-9) are potent irreversible inhibitors of Electrophorus electricus acetylcholinesterase. Carbamates 1-9 act as the peripheral anionic site-directed irreversible inhibitors of acetylcholinesterase by the stop-time assay in the presence of a competitive inhibitor, edrophonium. Linear relationships between the logarithms of the dissociation constant of the enzyme inhibitor adduct (Ki), the inactivation constant of the enzyme-inhibitor adduct (k2), and the bimolecular inhibition constant (k(i)) for the inhibition of Electrophorus electricus acetylcholinesterase by carbamates 1-9 and the Hammett substituent constant (sigma), are observed, and the reaction constants (ps) are -1.36, 0.35 and -1.01, respectively. Therefore, the above reaction may form a positive charged enzyme-inhibitor intermediate at the peripheral anionic site of the enzyme and may follow the irreversible inactivation by a conformational change of the enzyme.

Acetylcholinesterase↗
PubMed2001

On-column trace enrichment by sequential frontal and elution electrochromatography. 1. Application to carbamate insecticides.

An on-column trace enrichment method for CEC of dilute samples is presented. The method involves on-line preconcentration by frontal electrochromatography under conditions of strong solute binding to the stationary phase followed by a step-gradient elution electrochromatography with a mobile phase of high eluting strength. This method is tested with dilute samples of carbamate insecticides using capillary columns of 100-microm i.d. packed with a 5-microm octadecyl silica (ODS) stationary phase. The effectiveness of on-line preconcentration (i.e., zone narrowing) depends on the retention factor, k', of the analyte in the injection solvent as well as in the eluting mobile phase (i.e., the organic solvent content), the applied voltage during sample introduction, and elution and length of the introduced sample plug. Under optimal frontal and elution electrochromatography conditions, a 500-fold sensitivity increase is achieved for carbofuran (a carbamate insecticide) with a UV detector. The method is demonstrated with deionized and tap water samples spiked with carbamate insecticides.

Carbamates↗
PubMed1996

Selective inhibition of N-formylpeptide-induced neutrophil activation by carbamate-modified peptide analogues.

Stimulation of the leukocyte N-formylpeptide receptor (FPR) induces chemotaxis, cell adhesion, free radical release, and degranulation, responses associated with infection and inflammation. Under conditions where continuous activation of the receptor prevails, neutrophil-dependent tissue damage ensues. Antagonists of the FPR have potential for use as diagnostic and therapeutic agents. Hence, we have synthesized and evaluated a series of amino-terminal carbamate analogues of the peptide Met-Leu-Phe (MLF) in order to determine the structural requirements for imparting agonist or antagonist activity at the human neutrophil FPR. Peptides were evaluated in three in vitro assays: receptor binding, superoxide anion release, and cell adhesion. Unbranched carbamates (methoxycarbonyl, ethoxycarbonyl, and n-butyloxycarbonyl) resulted in agonist activity, whereas branched carbamates (iso-butyloxycarbonyl, tert-butyloxycarbonyl, and benzyloxycarbonyl) were antagonists. The peptide antagonists were more potent inhibitors of superoxide anion release than cell adhesion by 4-7-fold. When iso-butyloxycarbonyl-MLF (i-Boc-MLF) was further modified at the carboxy terminus with Lys, antagonist potency was retained but without functional selectivity. Further C-terminal modification with the radionuclide linker diethylenetriaminepentaacetic acid did not alter the potency of i-Boc-MLFK. These results indicate that the switch from agonist to antagonist activity can be achieved by modifying the overall size and shape of the amino-terminal group; that modifications at both the amino and carboxy termini can alter the functional selectivity of the peptide; and that modifications can be tolerated at the carboxy terminus to allow for development of an antagonist for diagnostic applications.

Adult↗
PubMed2004

A simple and rapid assay for analyzing residues of carbamate insecticides in vegetables and fruits: hot water extraction followed by liquid chromatography-mass spectrometry.

A simple, specific, and rapid analytical method for determining seven largely used carbamate insecticides in tomato, spinach, lettuce, zucchini, pear, and apple is here presented. This method is based on the matrix solid-phase dispersion technique, with heated water as extractant followed by liquid chromatography (LC)-mass spectrometry (MS) equipped with a single quadrupole and an electrospray ion source. Target compounds were extracted from the vegetal matrixes by water heated at 50 degrees C. After acidification and filtration, 0.25 mL of any aqueous extract was injected in the LC column. MS data acquisition was performed in the selected ion monitoring mode, selecting three ions for each target compound. Heated water appeared to be an excellent extractant because recovery data ranged between 76 (carbaryl in spinach) and 99% (pirimicarb in spinach), with RSDs not larger than 10%. Using trimethacarb (an obsolete carbamate insecticide) as a surrogate internal standard, the accuracy of the analysis varied between 84 and 110%, with RSDs not larger than 9%. On the basis of a signal-to-noise ratio of 10, limits of quantification were estimated to range between 2 (pirimicarb) and 10 ppb (oxamyl) and were not influenced by the type of matrix. When trying to fractionate analytes by using a short chromatographic run time, marked weakening of the ion signals for oxamyl, methomyl, and aldicarb were observed. This effect was traced to polar endogenous co-extractives eluted in the first part of the chromatographic run that interfered with gas-phase ion formation for carbamates. Adopting more selective chromatographic conditions eliminated this effect.

Carbamates↗
PubMed1994

Geiparvarin analogues. 4. Synthesis and cytostatic activity of geiparvarin analogues bearing a carbamate moiety or a furocoumarin fragment on the alkenyl side chain.

As a continuation of previous studies on the synthesis and antitumor activity of geiparvarin analogues bearing a carbamate moiety in the alkyl side chain, a series of N-substituted [(E)-3-(4,5-dihydro-5,5-dimethyl-4-oxo-2-furanyl)-2- butenyl]carbamates (15a-f) were synthesized and tested with the objective to investigate the reason for the marked difference of cytostatic activity found between alkyl and phenyl derivatives. A series of compounds, characterized by different physicochemical properties, were designed in order to study this hypothesis. Moreover, to further investigate the modification of the alkenyl side chain, (E)- and (Z)-[2-(4,5-dihydro-5,5-dimethyl-4-oxo-2-furanyl)propenyl]-7H-furo[3,2- g][1]benzopyran-7-one (11a,b) were synthesized, the latter compounds being the combination of two units, namely, the 3(2H)-furanone ring system endowed with potent alkylating properties and the furocoumarin portion which binds to DNA resulting in potential DNA-targeted alkylating agents. The compounds were tested for their cytostatic activity against proliferation of murine (L1210) and human (Molt/4, CEM, or MT-4) tumor cells. The highest cytostatic activity found within both series of carbamic derivatives (15a-d,k and 15e,g-j) was associated with the highest global lipophilicity. With regard to compounds 11a,b, the cytostatic activity of (Z)-furocoumarin 11b might be related to a specific interaction with DNA (i.e., intercalation).

Animals↗
PubMed1991

Dual-action cephalosporins: cephalosporin 3'-quinolone carbamates.

A series of cephalosporins has been prepared in which the 3'-position was linked to the nitrogen of the antibacterial quinolone ciprofloxacin through a carbamate function. Like the ester-linked and quaternary-linked dual-action cephalosporins reported earlier, these carbamate-linked compounds exhibited a broad antibacterial spectrum derived from both cephalosporin-like and quinolone-like activities, suggesting a dual mode of action. Studies to elucidate details of the mechanism of action have been inconclusive. Ciprofloxacin liberated as a consequence of bacterial enzyme-mediated reactions may contribute to the second mode of action, although some evidence indicates that the intact carbamate-linked bifunctional molecules may possess intrinsically both beta-lactam and quinolone activities.

Animals↗
PubMed1984

Syntheses and anthelmintic activity of alkyl 5(6)-(substituted-carbamoyl)- and 5(6)-(disubstituted-carbamoyl)benzimidazole-2-carbamates and related compounds.

A number of alkyl 5(6)-(substituted-carbamoyl)- and 5(6)-(disubstituted-carbamoyl)benzimidazole-2-carbamates and related compounds have been synthesized, and their anthelmintic activity against various intestinal helminths of experimental animals have been evaluated. A large percentage of the compounds synthesized showed noteworthy activity against Ancylostoma ceylanicum and at higher doses against Hymenolepsis nana infections. Compared to the alkyl 5(6)-(substituted-carbamoyl)benzimidazole-2-carbamates, the disubstituted carbamoyl analogues were found to exhibit better anthelmintic activity. The most active compound of the series, namely, methyl 5(6)-[(N-2-pyridylpiperazino)carbamoyl]benzimidazole-2-carbamate (90), has been screened against intestinal helminths in higher animals and as a micro- and macrofilaricidal agent. Compound 90 has been identified as a broad-spectrum anthelmintic agent. Compound 90 has been identified as a broad-spectrum anthelmintic in view of its efficacy against A. ceylanicum (hamsters and dogs), H. nana (rats), Nippostrongylus brasiliensis (rats), Syphacia obvelata (mice), A. tubaeformis (cat), Toxocara spp. (cat), and Litomosoides carinii (cotton rat).

Ancylostomiasis↗
PubMed1988

(Acyloxy)alkyl carbamates as novel bioreversible prodrugs for amines: increased permeation through biological membranes.

(Acyloxy)alkyl carbamates of the type R1R2N-CO-O-CHR3-OCO-R4 are described as novel bioreversible prodrugs for primary and secondary amines. These were prepared either by a one-step reaction involving nucleophilic attack on p-nitrophenyl alpha-(acyloxy)alkyl carbonates with displacement of p-nitrophenol or by reaction of alpha-haloalkyl carbamates with silver or mercury salts of carboxylic acids. Enzymatic hydrolysis of the ester bond in these ester carbamates leads to a cascade reaction resulting in rapid regeneration of the parent amine. Permeability measurements of such nonionic derivatives of atenolol, betaxolol, pindolol, propranolol, and timolol through fuzzy rat skin and rabbit cornea mounted on diffusion cells show that derivatization of the hydrophilic beta-blockers results in several-fold increase in permeation through these biological membranes. However, prodrug modification of the lipophilic beta-blockers leads to little advantage in permeability characteristics.

Adrenergic beta-Antagonists↗
PubMed2006

Design, synthesis, and preliminary evaluation of doxazolidine carbamates as prodrugs activated by carboxylesterases.

The synthesis and tumor cell growth inhibition by doxazolidine carbamate prodrugs are reported. The carbamates were designed for selective hydrolysis by one or more human carboxylesterases to release doxazolidine (Doxaz), the formaldehyde-oxazolidine of doxorubicin that cross-links DNA to trigger cell death. Simple butyl and pentyl, but not ethyl, carbamate prodrugs inhibited the growth of cancer cells that overexpress carboxylesterase CES1 (hCE1) and CES2 (hiCE). Relative CES1 and CES2 expression levels were determined by reverse transcription of the respective mRNAs, followed by polymerase chain reaction amplification. More complex structures with a p-aminobenzyl alcohol (PABA) self-eliminating spacer showed better growth inhibition (IC50=50 nM for Hep G2 liver cancer cells) while exhibiting reduced toxicity toward rat cardiomyocytes, relative to the parent drug doxorubicin. Pentyl 4-(N-doxazolidinylcarbonyloxymethyl)phenylcarbamate, the lead compound for further investigation, appears to be activated in Hep G2 cells that express both CES1 and CES2.

Animals↗
PubMed1996

Investigation of (Oxodioxolenyl)methyl carbamates as nonchiral bioreversible prodrug moieties for chiral amines.

The preparation of (oxodioxolenyl)methyl carbamates and their evaluation as novel nonchiral prodrug moieties for chiral primary and secondary amino functional drugs are described. 4-(Carbamoylmethyl)-2-oxo-1,3-dioxolene derivatives of 3,4-dimethoxyphenethylamine with 5-methyl, 5-phenyl, and 5-anisyl substitution (5a, 5b, and 5c) on the dioxolenone ring were prepared as model amine prodrugs by a one step process involving displacement of p-nitrophenol from appropriately substituted ring opening of these carbamates led to a cascade reaction resulting in the rapid and quantitative regeneration of the parent amine drug. Aryl substitution did not significantly alter the hydrolysis rates of these dioxolenone carbamates in buffers at pH 1 and 7.4 or in rat plasma, although the hydrolysis rates of 5-phenyl- (1b) and 5-anisyl- 4-methyl-1,3-dioxol-4-en-2-one (1c) in pH 7.4 phosphate buffer were 2-3 fold faster than that of the 5-methyl-substituted analog (1a). Application of this prodrug strategy to the chiral fibrinogen receptor antagonist L-734,217 resulted in a prodrug that gave quantitative reconversion in rat and dog plasma in vitro and oral bioavailability of 23 +/- 6% in dogs for the parent drug.

Amines↗
PubMed1998

Anhydrolide macrolides. 1. Synthesis and antibacterial activity of 2,3-anhydro-6-O-methyl 11,12-carbamate erythromycin A analogues.

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-carbamate analogues have been synthesized and evaluated for antibacterial activity. These compounds were found to be potent antibacterial agents against Gram-positive organisms in vitro, many having MIC values below 1 microg/mL for the macrolide-susceptible Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae, as well as improved activity compared to erythromycin A against the inducibly MLS (macrolide, lincosamide, and streptogramin B)-resistant organisms. Structure-activity studies revealed that arylalkyl carbamates with two and four carbon atoms between the aromatic moiety and carbamate nitrogen have the best in vitro activity. All of the C-10 epi analogues evaluated were found to have substantially less activity than the corresponding natural C-10 isomer. Several analogues demonstrated moderate antibacterial activity against the constitutively resistant S.aureus A-5278, S. pneumoniae5979, and S.pyogenes 930. However, despite potent in vitro activity, these analogues showed only moderate in vivo activity in mouse protection studies.

Animals↗
PubMed2004

Rhodium(II)-catalyzed aziridination of allyl-substituted sulfonamides and carbamates.

Several unsaturated sulfonamides underwent intramolecular aziridination when treated with PhI(OAc)(2), MgO, and catalytic Rh(2)(OAc)(4) to give bicyclic aziridines in excellent yield. Treatment of the resulting azabicyclic sulfonamides in methanol in the presence of p-TsOH resulted in exclusive opening of the aziridine ring at the most substituted position affording six- and seven-membered ring products in high yield. In contrast, the intramolecular aziridination of several cycloalkenyl-substituted carbamates did not require a Rh(II) catalyst and proceeded via an iminoiodinane intermediate. The resulting tricyclic aziridines underwent ring opening when treated with various nucleophiles to give anti-derived products as expected for nucleophilic attack at the three-membered ring. The iodine(III)-mediated reaction of a 3-indolyl-substituted carbamate, however, required a Rh(II) catalyst. The expected aziridine was not observed, but rather simultaneous spirocyclization of C(3) and stereoselective syn-acylation at C(2) occurred to give compound 41, whose structure was unequivocally established by an X-ray crystallographic study. The reaction proceeds in a stepwise manner via a metal-free zwitterionic intermediate which is attacked by a nucleophilic reagent on the same side of the amide anion. Related reactions occurred with both a 2-indolyl- and 3-benzofuranyl-substituted carbamate but with lower stereoselectivity.

Aziridines↗
PubMed2005

Practical synthesis of unsymmetrical ureas from isopropenyl carbamates.

A very convenient method for the synthesis of unsymmetrical ureas is described, based on isopropenyl carbamates. The synthetic efficiency of traditional methods for urea formation, such as use of phosgene or alkyl and aryl carbamates, is limited by the formation of symmetrical urea side products or reaction reversibility. Isopropenyl carbamates react with amines cleanly and irreversibly and give unsymmetrical ureas in high yield and purity. This method is ideal for the rapid synthesis of compound libraries.

Carbamates↗
PubMed2006

Aqueous phosphoric acid as a mild reagent for deprotection of tert-butyl carbamates, esters, and ethers.

Aqueous phosphoric acid (85 wt %) is an effective, environmentally benign reagent for the deprotection of tert-butyl carbamates, tert-butyl esters, and tert-butyl ethers. The reaction conditions are mild and offer good selectivity in the presence of other acid-sensitive groups, including CBZ carbamates, azetidine, benzyl and methyl esters, TBDMS, and methyl phenyl ethers. The mildness of the reaction is further demonstrated in the synthesis of clarithromycin derivative, in which a tert-butyl ester is removed in the presence of cyclic carbamate, lactone, ketal, acetate ester, and epimerizable methyl ketone functionalities. The reaction preserves the stereochemical integrity of the substrates. The reactions are high yielding, and the workup is convenient.

Carbamates↗
PubMed2005

Conformational pseudopolymorphism and orientational disorder in two-dimensional alkyl carbamate crystals.

The structures of self-assembled physisorbed monolayers of alkyl carbamates were examined with atomic detail by scanning tunneling microscopy at the liquid-solid interface. Through systematic variation of molecular structure, the factors determining the two-dimensional crystal packing and dynamics of alkyl carbamate monolayers were isolated. Two different conformational pseudopolymorphs on the surface were observed and their order of stability was varied by changing the length of the alkyl groups. The relative size of the two alkyl groups in a molecule affected the frequency of orientational flipping within a column, which in turn, exerts an influence on the relative orientation of the two-dimensional crystalline domains. These phenomena were explained on the basis of the preferred hydrogen-bonding geometry of the carbamate functional group and the different degree of van der Waals interaction for each form.

Alkanes↗