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PubMed1991

Heated linoleic acid anilide reduces serum enzyme activities in rats.

In view of possible involvement of fatty acid anilides in toxic oil syndrome (TOS), the effects of linoleic acid anilide (LAA) and heated linoleic acid anilide (HLAA) on the activities of serum enzymes following their oral administration was studied in rats as a function of time. Serum glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activities decreased significantly in both LAA and HLAA treated rats at day 4. The decreases, however, were confined to only HLAA treated group at later stages with GOT activity showing significant decrease at day 8 and total lactate dehydrogenase (LDH) as well as GOT and GPT activities at day 12. Liver GOT activity at day 4 and LDH activity at day 8 decreased significantly in both LAA and HLAA treated rats. These findings indicate HLAA components may interact with plasma membranes and thereby, reducing the secretion of the enzymes into the serum.

Alanine Transaminase↗
PubMed1984

Biological activity of 4-hydroxyisophthalic acid derivatives. II. Anilides with antimicrobial activity.

A series of 1,3 -bis-anilides of 4-hydroxyisophthalic acid was prepared and tested for antibacterial and antifungal activity. The prepared compounds (I-XVIII), of general structure (A), (Formula: see text) where Xn = H (I); 2-F (II); 3-F (III); 4-F (IV); 2-Cl (V); 3-Cl (VI); 4-Cl (VII); 2-Br (VIII); 3-Br (IX); 4-Br (X); 2-J (XI); 3-J (XII); 4-J (XIII); 2,5-Cl2 (XIV); 2,4-Br2 (XV); 2,3,4-Cl3 (XVI), 2,4,5-Cl3 (XVII); 2,4,6-Cl3 (XVIII), were investigated for the purpose of determining the effect of halogen-substitution on the aniline rings of (A). All of these compounds were prepared in satisfactory hield by reaction of 4-hydroxyisophthalic acid with the appropriate aromatic amine at 175 degrees for 3 hours. The 1,3-bis-anilides prepared in this investigation were screened for antimicrobial activity by a disk-diffusion assay (Kirby-Bauer modified). The organisms used were laboratory cultures of S. aureus, B. subtilis, B. anthracis, M. paratuberculosis 607, E. coli Bb, S. typhi, S. typhimurium, S. paratyphi B, Pr. vulgaris, Kl. pneumoniae, Ps. aeruginosa, C. albicans, and A. niger. The results of this investigation indicated that most of the 1,3-bis-(halogen-anilides) of 4-hydroxyisophthalic acid had little or no antifungal activity "in vitro", while showed significant activity against Gram+ and Gram- bacteria. Some fluoro-derivatives showed inhibitory activity especially toward S. aureus and M. paratuberculosis. Iodo-derivatives showed broad-spectrum "in vitro" antimicrobial activity, and had some antifungal activity.

Anilides↗
PubMed1995

Preparation and pharmacological activities of homolupinanoyl anilides.

On the pattern of well known dialkylaminoacyl anilides, a set of N-homolupinanoyl anilides was prepared and subjected to a broad pharmacological screening with in vivo and in vitro assays. As expected most compounds exhibited a strong antiarrhythmic activity, often comparable or superior to that of lidocaine and quinidine. Compound 1 exhibited an unusual profile as antiarrhythmic, being devoid of local anesthetic activity, calcium channel and beta adrenoceptor antagonism. Calcium channel blocking activity was seen in all aminobenzophenone derivatives, but not in the simpler anilides. Noteworthy are also the capacity of compound 7 to protect mice from a lethal dose of KCN, the moderate antihypertensive activity of 10 and, above all, the antagonism to guinea pig ileum contractile responses induced by several agents exhibited by compound 11, which deserves further investigation for a potential use in irritable bowel syndrome. Compound 11 showed also good relaxant activity on tracheal strips and inhibitory activity against arachidonate induced platelet aggregation. Finally, compound 11 displaced several radioligands from their respective binding sites. Most potent was displacement of [3H]pirenzepine (IC50 < or = 0.01 microM) from M1 binding sites of rat brain, while displacement of [3H] methylscopolamine from rat heart (M2) and submaxillary salivary glands (M3) preparations was much weaker (IC50 approximately equal to 2.4 and 1.3 microM, respectively).

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1976

[Microbial breakdown of acid anilide fungicides (author's transl)].

o-Toluylanilide, 2.5-dimethylfuran-3-carboxanilide, 5.6-dihydro-2-methyl-1.4-oxathiine-3-carboxanilide and other acid anilides are systemic fungicides which act selectively on rusts and smuts. From garden soil a Nocardia sp. was isolated which can grow with acid anilide fungicides as the only source of carbon. From this Nocardia sp. it was possible to produce mutants which are blocked genetically at various steps of the breakdown pathway of these acid anilide fungicides. It was possible to follow the breakdown pathway with the aid of accumulates of the rough I strain and of the mutants as well as by growth and enzyme tests. Breakdown starts with hydrolytic splitting of the acid amide bond by an acylamidase. The acid components of the fungicides are accumulated in the medium; they do not affect the growth. The aniline component is oxidized to pyrocatechol by a dioxygenase. Methyl and chloro-derivatives of aniline which are formed in the soil due to the hydrolysis of herbicides and fungicides, are also converted into the respective pyrocatechol derivatives. By orthocleavage cis-cis muconic acid forms from pyrocatechol. This compound is metabolized into succinate and acetyl CoA via the beta ketoadipate pathway.

Amidohydrolases↗
PubMed2001

Nonlinear free energy relationship in the general-acid-catalyzed acylation of rat kidney gamma-glutamyl transpeptidase by a series of gamma-glutamyl anilide substrate analogues.

The gamma-glutamyl transpeptidase (GGT) purified from rat kidney reacts with a series of eight parasubstituted L-glutamyl gamma-anilides, in the presence of Gly-Gly, catalyzing the formation of gamma-Glu-Gly-Gly (pH 8.0, 37 degrees C). The transpeptidation reaction was followed through the discontinuous colorimetric determination of the concentration of released parasubstituted aniline. Steady-state kinetic studies were performed to measure k(cat) and K(M) values for each anilide substrate. A Hammett plot constructed by the correlation of log(k(cat)) and the sigma(-) parameter for each anilide substrate displays statistically significant upward curvature, consistent with a general-acid-catalyzed acylation mechanism in which the geometry of the transition state changes with the nature of the para substituent. Kinetic isotope effects were measured and are consistent with a reaction involving a proton in flight at the rate-limiting transition state. The pH-rate profiles measured over pH 7.0-9.5 are bell-shaped with kinetic pK(a) values that may be attributed to the active site nucleophile (or its general-base catalytic partner) and the active-site general acid. The variation of the latter pK(a) value as a function of temperature is consistent with an enthalpy of ionization expected for an ammonium ion acting as a general acid. Examination of the variation of k(cat) as a function of temperature gave values for the enthalpy and entropy of activation that are similar to those determined for the general-acid-catalyzed breakdown of the tetrahedral intermediate formed during acylation of chymotrypsin by similar amide substrates.

Acylation↗
PubMed1992

Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Identification and structure-activity relationships of a novel series of fatty acid anilide hypocholesterolemic agents.

A series of fatty acid anilides was prepared, and compounds were tested for their ability to inhibit the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) in vitro and to lower plasma total cholesterol and elevate high-density lipoprotein cholesterol in cholesterol-fed rats in vivo. The compounds reported were found to fall into two subclasses with different anilide SAR. For nonbranched acyl analogues, inhibitory potency was found to be optimal with bulky 2,6-dialkyl substitution. For alpha-substituted acyl analogues, there was little dependence of in vitro potency on anilide substitution and 2,4,6-trimethoxy was uniquely preferred. Most of the potent inhibitors (IC50 less than 50 nM) were found to produce significant reductions in plasma total cholesterol in cholesterol-fed rats. Additionally, in vivo activity could be improved significantly by the introduction of alpha,alpha-disubstitution into the fatty acid portion of the molecule. A narrow group of alpha,alpha-disubstituted trimethoxyanilides, exemplified by 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (39), was found to not only lower plasma total cholesterol (-60%) in cholesterol-fed rats but also elevate levels of high-density lipoprotein cholesterol (+94%) in this model at the screening dose of 0.05% in the diet (ca. 50 mg/kg).

Animals↗
PubMed1983

Anilides related to substituted benzamides. Potential antipsychotic activity of N-(4-amino-5-chloro-2-methoxyphenyl)-1-(phenylmethyl)-4-piperidinecarboxamide.

The substituted benzamides are used clinically both as antipsychotics and as stimulants of gastric motility. The antipsychotic effects are considered to be a consequence of their central dopamine antagonist properties, but there is evidence that the gastric stimulatory effects may be mediated by other mechanisms. Clebopride (3) is a substituted benzamide that although marketed for its stimulatory effects on gastric motility, is also a potent central dopamine antagonist. The corresponding anilide, BRL 20596 (4a), where the amide bond has been reversed, has been synthesized and found to lack gastric stimulatory activity. However, the potent central dopamine antagonist activity is retained, suggesting that benzamides and anilides have similar affinities for central dopamine receptors. The implications of the conformations adopted by benzamides and anilides at such receptors are discussed. Evidence is also presented that there is a further lipophilic binding site on such receptors for which the N-benzyl group is an optimal fit.

Animals↗
PubMed2002

Asymmetric synthesis of axially chiral benzamides and anilides by enantiotopic lithiation of prochiral arene chromium complexes.

Axially chiral benzamides and anilides were prepared by enantiotopic lithiation at the distinguished benzylic methyl of prochiral tricarbonylchromium complexes of N,N-diethyl 2,6-dimethylbenzamide (1) and N-methyl-N-acyl 2,6-dimethylaniline (14 and 21) with a chiral lithium amide base followed by electrophilic substitution in good yields with high optical purity. The resulting axially chiral chromium-complexed benzamides and anilides were oxidized under air to give chromium-free axially chiral benzamides and anilides in an enantiomerically active form without axial bond rotation at room temperature.

Journal Article↗
PubMed1995

Zeneca ZD6169 and its analogs from a novel series of anilide tertiary carbinols: in vitro KATP channel opening activity in bladder detrusor.

The potassium (K+) channel opening activity of Zeneca ZD6169 and one of its pyridylsulfonyl analogs from the anilide tertiary carbinol series was ascertained. Their mechanoinhibitory effects on the myogenic activity of the guinea pig bladder detrusor muscle were measured in a set of functional assays. Elevating the K+ concentration in the tissue bath from 15 to 80 mmol/l increased the IC50 value of ZD6169 from 1.61 +/- 0.22 223 +/- 37 mumol/l. This result suggests that ZD6169 may act as a K+ channel opener. Similar to the prototypic ATP-sensitive K+ (KATP) channel opener cromakalim, the K+ channel openers from the anilide tertiary carbinol series displayed stereoselective mechanoinhibitory activity only in the test protocol in which the detrusor was stimulated with 15 mmol/l KCl. Being the active enantiomer, ZD6169 has an activity more than 30-fold higher than the less active enantiomer. ZD6169 at 10 mumol/l hyperpolarized the guinea pig detrusor membrane potential by 6.1 +/- 1.2 mV and increased the whole cell KATP current in isolated guinea pig smooth muscle cells by 34.9 +/- 7.9 pA. This is comparable to the increase of 26.8 +/- 5.0 pA obtained with 10 mumol/l of lemakalim, the active enantiomer of cromakalim. The K+ channel opening activity of ZD6169 and the pyridylsulfonyl analog was competitively antagonized by the KATP channel blocker glibenclamide in the guinea pig detrusor with a pA2 value of 7.2. This activity, however, was unaffected by blockers of small and large conductance Ca-dependent K+ channels, such as apamin and charybdotoxin, respectively. The present study showed that Zeneca ZD6169 and its analog from the anilide tertiary carbinol series are K+ channel openers that activate KATP channels in vitro to relax bladder detrusors.

Adenosine Triphosphate↗
PubMedDate not supplied

Acetohydroxyacid synthase inhibitors: N-phthalyl-L-valine anilide and related compounds.

The potency of L-valine as an inhibitor of Zea mays acetohydroxyacid synthase (AHAS) is increased more than 8000-fold on conversion to its N-phthalyl anilide derivative which is active at 2 microM. The D-valine, alpha-aminobutyric acid, isoleucine and phenylalanine analogs are 11- to 43-fold less potent, and similar N-phthalyl anilide derivatives of other branched-chain amino acids are essentially inactive. Full potency is retained on replacing the phthalimide moiety of the valine anilide with cyclohexane-1,2-dicarboximide or 1-cyclohexene-1,2-dicarboximide groups and partial activity with 4-cyclohexene-1,2-dicarboximide and methyl- or dimethylmaleimide groups. Inhibition of the enzyme and of root growth by the valine derivatives may result from binding at or near the site involved in feedback control of AHAS by L-valine.

Acetolactate Synthase↗
PubMed1987

Studies on the derivatives of aziridine. II. Synthesis and immunopharmacological analysis of substituted amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid.

Several new amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid were synthetized. The beta-/p-chlorobenzoyl/-acrylic acid 2 was used as the substrate. This compound was converted by reaction with appropriate amine into amides and anilides of beta-/p-chlorobenzoyl/-acrylic acid (3-10). These compounds react with ethylenoimine giving appropriate amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid (11-18). When pharmacologically analyzed, they appeared to possess marked immunotropic activity. The derivatives in question modulated both humoral as well as cellular immune response, the effect being related to the type of substitutent in the amide group.

Animals↗
PubMed1984

[2-(Guanidino)-anilides and related compounds. Synthesis and anthelmintic effect. 3. Anthelmintics].

Anilides bearing a guanidino, thioallophanato, isothioallophanato or amidino group in the ortho position were synthesised (6) for investigations of their anthelmintic effects, and tested against sheep trichostrongylides. The most active anilides are those containing a 5-alkylthio, 5-alkylsulphinyl (alkyl = C3H7, C4H9), 5-phenylthio, 5-phenylsulphinyl or 4-phenylsulphonyloxy group, and a guanidino group substituted at both nitrogen atoms by a methoxycarbonyl group. The most active anthelmintic anilides are the form-, propion-, butyr- and methoxy-acetanilides (e.g. 60, 61, 66, 95, 100, 110). Of the guanidines unsubstituted at N' and N", the 2-guanidino-5-phenylthio-2-methoxyacetanilide (123) and the 2-guanidino-5-phenylsulphinyl-2-methoxyacetanilide (152) were more active than parbendazole. From the class of bismethoxycarbonylguanidines (6 alpha), which are also the most interesting products in terms of stability, febantel (110, Rintal) has been introduced into veterinary practice for the treatment of nematode infections in horses, cattle, sheep and swine.

Aniline Compounds↗
PubMed1991

Toxicity of oleic acid anilide in rats.

In the present investigation, we have studied the toxic potential of oleic acid anilide (OAA) and heated oleic acid anilide (HOAA) in relation to the toxic oil syndrome (TOS). Male Sprague-Dawley rats were given 250 mg/kg of OAA or HOAA in mineral oil by gavage, on alternate days for 2 weeks (total 7 doses). The control rats received an equal volume of mineral oil only. The animals were sacrificed at days 1, 7, and 28 following the last dose. Ratio of organ-to-body weight showed increases in spleen and kidney of HOAA and OAA treated rats, respectively, at day 1 while this ratio for liver in HOAA treated group showed a decrease at day 1. Among blood parameters, white blood cells increased in HOAA treated group at day 1 and in both OAA and HOAA groups at day 28. Mean corpuscular hemoglobin (MCH) and mean cell volume (MCV) also showed increases in the HOAA treated rats at days 7 and 28. Serum lactate dehydrogenase (LDH) decreased in both OAA and HOAA treated rats at day 1, while at day 7 the decrease was confined only to the HOAA group. Serum glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activities also decreased at most of the time points. Liver mitochondrial ATPase activity decreased in the HOAA group at day 7 and in the OAA group at day 28. Among serum immunoglobulins, IgA levels increased throughout the study but the changes were more pronounced in HOAA treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1999

The acute pathology of fatty acid anilides and linoleic diester of 3-phenylamino-1,2-propanediol in mice: possible implication as aetiologic agents for the toxic oil syndrome.

Two groups of compounds, the fatty acid anilides and the mono- and diester of 3-phenylamino-1,2-propanediol (PAP) are suspected as aetiologic agents for the toxic oil syndrome (TOS). Intraperitoneal administration of oleoyl and linoleoyl anilides in mice caused severe weight loss followed by death in 50% of the animals and histopathological changes mainly to the lungs. Linoleic diester of PAP led to weight loss, haemorrhage, congestion and emphysema in the lungs and an increase in blood eosinophilia. Although not producing the full spectrum of symptoms the effects of the substances resemble the acute human disease. Possibly, the two groups of substances led together to the full spectrum of disease manifestations seen in TOS.

Anilides↗
PubMed1983

Effect of fatty acid anilides on the generation of arachidonic acid by human polymorphonuclear leukocytes.

The addition of oleoylanilide or linoleylanilide to human polymorphonuclear leukocytes induces a time- and dose-dependent generation of arachidonic acid. Half-maximal effect is caused by a dose of 0.2 mg linoleylanilide/ml. Fatty acid anilides also produce a time- and dose-dependent inhibition of the synthesis of triacylglycerol. Half-maximal effect is caused by 1 microgram linoleylanilide/ml. These results indicate that fatty acid anilides, which have been found in the illegal cooking oil which intoxicated thousands of Spaniards, alter lipid metabolism in human polymorphonuclear leukocytes.

Anilides↗
PubMedDate not supplied

Distribution and excretion of orally administered oleic acid anilide in the rat.

Oleic acid anilide [aniline-14C(U)] was administered by gastric tube to male rats in a single dose (10 mg/kg body weight). After intervals of 3, 6, 24 or 120 h the excretion of radioactivity and the distribution in different organs were studied. The radioactivity was eliminated rapidly through the urine and faeces containing 62% and 38%, respectively, after 24 h. At this time the excretion was almost complete. No radioactivity could be found in the expired air. The absorbed oleic anilide was easily deacylated as evidenced by the excretion of N-acetyl-p-aminophenol conjugate as the main urinary metabolite representing 60-70% of the urinary radioactivity. The radioactivity in faeces was due to the unchanged substance. Twenty-four hours after administration only 0.7% of the dose remained in the total organism with the highest concentrations in the red blood cells, spleen and forestomach. Even after 5 daily doses, an accumulation of radioactivity could not be found.

Administration, Oral↗
PubMed1993

Effects of linoleic and oleic acid anilides on prostacyclin synthesis and fibrinolytic profile of human endothelial cells in culture: relevance to the toxic oil syndrome.

We evaluated the effects of fatty-acid anilides (FAA) on prostacyclin (PGI2) synthesis and on the fibrinolytic properties of human umbilical vein endothelial cells. Preincubation of endothelial cells with oleic- and linoleic-anilides (OAA and LAA, respectively) resulted in a time- and concentration-dependent inhibition of ionophore A23187- and thrombin-induced PGI2 synthesis. However, no significant effects of FAA on arachidonic acid-induced PGI2 synthesis were found, except with 1000 microM LAA which inhibited cyclooxygenase activity after 24 h. In general terms, OAA showed similar inhibitory effects on PGI2 production as did LAA, but with a shifted time course, since the production of PGI2 at 24 h for OAA was similar to that observed for LAA at 2 h. The release of labeled arachidonic acid from cell membranes was significantly reduced (75-85%), after 24 h, with both FAA. The effect of 100 microM LAA on thrombin-induced PGI2 production was rapid (within 15 min) and irreversible after 60 min. The recovery of PGI2 synthesis after LAA treatment was blocked by cycloheximide, suggesting a decrease of phospholipase(s) activity or cessation of enzyme synthesis. Moreover, this reduced PGI2 synthesis was not associated with [3H]adenine release. Our data indicate that FAA induce a significant impairment of stimulated PGI2 synthesis and arachidonic acid release in endothelial cells, acting primarily as inhibitors of phospholipase(s) rather than of cyclooxygenase. Finally, both LAA and OAA induce an anti-fibrinolytic activity in these cells where major changes are observed in the plasminogen activator inhibitor and the urine-type plasminogen activator.

Anilides↗
PubMed1995

Bioisosterism in drug design: identification of and structure-activity relationships in a series of glycine anilide ACAT inhibitors.

To examine the effects of bioisosteric replacement on the biological activity of our previously disclosed disubstituted urea inhibitors of the enzyme acyl-CoA:cholesterol acyltransferase (ACAT), we prepared a series of N'-substituted and N',N'-disubstituted glycine anilides. These compounds were tested for the ability to inhibit ACAT in vitro and lower plasma total cholesterol in cholesterol-fed rats given a single high-fat, high-cholesterol meal. ACAT inhibitory potency was greatest in compounds containing 2,6-diisopropyl substituents in the anilide portion with the glycine nitrogen substituted by a 1,1-diphenylmethyl moiety. Small improvements in potency in vitro were obtained by substitution of electron donating groups in the 2-, 3- or 5-positions of the aryl rings of the 1,1-diphenylmethyl moiety, but not by substitution in the 4-position. In vitro potency was maintained, but not improved by acylation of the glycine nitrogen. Through a QSAR analysis of in vitro ACAT inhibition for this set of compounds, an equation could be derived which accounted for 85% of the variance in the dataset. An optimal clogp of 6.65 was found, comparable to that found for other series of ACAT inhibitors. In general, compounds from this series displayed inhibitory potency against ACAT in vitro and hypocholesterolemic activity in the in vivo rat model of hypercholesterolemia comparable to that found with the ureas.

Acyl Coenzyme A↗