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At least 19 recordsLinked to original sources
PubMed1978

Metabolic and toxic behaviours of phthalimide derivatives in albino rat II. Placental passage of chloromethyl phthalimide, oxymethyl phthalimide and phthalimide--their fetal metabolism.

Chloromethyl phthalimide, oxymethyl phthalimide, and phthalimide are absorbed by the albino rat at a comparatively high rate. Only phthalimide, the metabolic product, will be recordable from fetuses, following oral administration of chloromethyl phthalimide and oxymethyl phthalimide topregnant rats. Those findings, in conjunction with metabolic studies applied to fetuses isolated by caesarian section, appear to suggest the occurrence of an intensive metabolism in fetal tissue. Certain differences established between results of thin-layer chromatography, on the one hand, and 15N studies, on the other, are likely to support the assumption that phthalimide is further metabolised by splitting the imide ring yielding phthalamic acid.

Animals↗
PubMed1983

Hypolipidemic activity of phthalimide derivatives. 3. A comparison of phthalimide and 1,2-benzisothiazolin-3-one 1,1-dioxide derivatives to phthalimidine and 1,2-benzisothiazoline 1,1-dioxide congeners.

Previously it has been observed that N-substituted phthalimide derivatives with chain lengths of four carbon or oxygen atoms showed potent hypolipidemic activity in rodents at 20 (mg/kg)/day ip. The 1,2-benzisothiazolin-3-one 1,1-dioxide (saccharin) nucleus, itself, had also been observed to be active at the same dose. An investigation was undertaken to examine a series of 1,2-benzisothiazolin-3-one 1,1-dioxide analogues for their hypolipidemic activity in mice and to compare them to their respective phthalimide congeners. In addition, a series of 1,2-benzisothiazoline 1,1-dioxide and phthalimidine analogues was prepared, and their hypolipidemic activity was compared to the phthalimide analogues. These studies show that the respective congeners of 1,2-benzisothiazolin-3-one 1,1-dioxide compared favorably to phthalimide congeners in reducing serum triglyceride and cholesterol levels in male CF1 mice at 20 (mg/kg)/day ip. Of the saccharin derivatives, 3-oxo-1,2-benzisothiazoline-2-propionic acid 1,1-dioxide was the most effective in lowering serum cholesterol levels by 53% after 16 days dosing and 3-oxo-1,2-benzisothiazoline-2-valeric acid 1,1-dioxide lowered serum triglycerides 56% after 14 days dosing. The 1,2-benzisothiazoline 1,1-dioxide and phthalimidine compounds were less active as hypolipidemic agents than their 1,2-benzisothiazolin-3-one 1,1-dioxide and phthalimide analogues, respectively.

Animals↗
PubMed1979

Hypolipidemic activity of phthalimide derivatives. 1. N-Substituted phthalimide derivatives.

The general lipid-lowering action of the N-substituted phthalimide derivatives reported herein, as well as the activity of potassium phthalimide, implicates the phthalimide moiety as possessing hypolipidemic activity in rodents. Compounds containing substituents with chain lengths of four carbon or oxygen atoms showed the best hypolipidemic activity in the series tested. Tests involving 1-N-phthalimidobutan-3-one demonstrated a dose-dependent hypolipidemic action free of estrogenic side effects, with no apparent deposition of cholesterol in body organs, and with a high therapeutic index. Further work on the hypolipidemic activity of phthalimido, as well as other imido compounds, is underway.

Animals↗
PubMed1989

Aqueous degradation of N-(hydroxymethyl)phthalimide in the presence of specific and general bases. Kinetic assessment of N-hydroxymethyl derivatives of nitrogen heterocycles as possible prodrugs.

The conversion of N-(hydroxymethyl)phthalimide (NHPH) to phthalimide could not be detected within 300 s at pH 9.0, whereas in 0.18 M NaOH complete conversion of NHPH to phthalimide was observed within 50 s. In the presence of 0.2-0.4 M 1,4-diazabicyclo[2.2.2]octane buffer solutions (pH 9.30-9.54), 40-60% conversion of NHPH to phthalimide occurred within 90-120 s. The initial concentration of NHPH affected the extent of conversion of NHPH to phthalimide.

Alkalies↗
PubMed1977

Gas chromatographic determination of some chlorothyl phthalimide compounds.

The use of small-bore glass columns packed with low liquid-phase-loaded insert supports has provided the capability for the separation and quantitative determination of a series of chloroethyl phthalimides. Compounds such as N-(2-chlorovinyl) and N-(1,2-DICHLOROETHYL) PHTHALIMIDE HAVE BEEN MEASURED WITH A RELATIVE STANDARD DEVIATION OF NO MORE THAN 1.4%. The N-(1-chloroethyl) phthalimide compound is not stable even in thisinert system, but it can be stabilized by the room temperature preparation of the N-(1-ethoxyethyl) phthalimide derivative. Methods of standards preparation, calibration, and analysis of N-(1,2-dichloroethyl) phthalimide reaction mixtures are presented.

Chromatography, Gas↗
PubMed1994

Anticonvulsant activity of some 4-amino-N-phenylphthalimides and N-(3-amino-2-methylphenyl)phthalimides.

A series of fifteen N-phenylphthalimides including 12 4-amino-N-phenylphthalimides and three N-(3-amino-2-methylphenyl)phthalimides was prepared and evaluated for anticonvulsant properties. The compounds were tested against seizures induced by electroshock (MES) and pentylenetetrazol (scPTZ) in mice dosed intraperitoneally. Their neurologic toxicity was assessed using the rotorod assay procedure. The most potent 4-amino-N-phenylphthalimides against MES were those possessing small lipophilic groups in either 2 or 2 and 6 positions of the N-phenyl ring. They also exhibited some activity against scPTZ and were the most toxic of the series. By contrast, no activity against scPTZ or neurotoxicity could be observed up to 300 mg/kg for members of the N-(3-amino-2- methylphenyl)phthalimide series. In this series, the order of anti-MES activity appears to correspond to the phthalimide ring substitution pattern of 4-amino > H > 4-methyl. Quantitation of anticonvulsant properties and toxicity of 4-amino-N-(2,6-dimethylphenyl)phthalimide (ADD 213063) previously initiated in rats has been, here, extended to mice dosed intraperitoneally but also orally. The confrontation of the two modes of administration in mice suggests that ADD 213063 presents with a good bioavailability.

Animals↗
PubMed1997

Tumor necrosis factor-alpha production-inhibiting activity of phthalimide analogues on human leukemia THP-1 cells and a structure-activity relationship study.

N-Substituted phthalimides (2-substituted 1H-isoindole-1,3-diones) were prepared and their inhibitory effects on tumor necrosis factor-alpha (TNF-alpha) production by human leukemia cell line THP-1 stimulated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or okadaic acid (OA) were examined. A structure-activity relationship study of these phthalimide analogues revealed that their inhibitory effects on TPA- and OA-induced TNF-alpha production by THP-1 cells are well correlated to each other, i.e. they may involve the same target molecule(s). An analysis by the use of phthalimide analogue-immobilized affinity gels indicated the existence of several phthalimide-binding proteins in THP-1 cell extract.

Drug Screening Assays, Antitumor↗
PubMed1984

Hypolipidemic activity of phthalimide derivatives. 7. Structure-activity studies of indazolone analogues.

The apparent benefit of limiting serum cholesterol and triglyceride levels either by dietary restriction or drug therapy has prompted work in our laboratories toward development of a suitable antihyperlipidemic agent. We have demonstrated the antihyperlipidemic activity of a series of phthalimide derivatives in rodents to be significantly greater than that of clofibrate at a dose of 20 mg/(kg day), intraperitoneally. Here we report the synthesis and biological evaluation of a series of indazolone derivatives, which are heterocycles that are structurally related to the phthalimides . In general, structure-activity relationships within the phthalimide series may be extended to the indazolones . While indazolone itself is only moderately active, N1-carbethoxy substitution produced a more active compound. Substitution of the N2 position with an n-butyl group afforded the most active compound, as also seen in the phthalimide series. Aromatic substitution with electron-releasing and -withdrawing groups lessened the antihyperlipidemic activity.

Animals↗
PubMed1990

Hypolipidemic activity of a series of N-pyridinyl and N-quinolinyl substituted derivatives of phthalimide and succinimides in rodents.

N-Pyridinyl- and N-quinolinyl-ethyl substituted succinimide and phthalimide derivatives demonstrated significant hypolipidemic activity in rodents lowering both serum cholesterol and triglyceride levels at 20 mg/kg.day i.p. The pyridinyl, quinolinyl and tetrahydro-2-quinolinyl substitution improved the hypolipidemic activity of the succinimide derivatives. Whereas select N-quinolinylethylphthalimide derivatives demonstrated less activity than phthalimide, itself, in lowering serum cholesterol and triglyceride levels, they did cause significant increases in HDL cholesterol and lower LDL cholesterol levels after 14 days of drug administration. Phthalimide actually caused reductions of HDL cholesterol levels in rats. These new agents with heterocyclic substitution of the N atom of phthalimide increased fecal excretion of lipids and suppressed in vitro hepatic rate limiting enzyme activities for de novo synthesis of cholesterol, fatty acids and triglycerides. Acute toxicity studies of the N-quinolinylethylphthalimide derivatives indicated that the agents are safe as potential therapeutic agents at doses necessary for hypolipidemic activity.

Animals↗
PubMed1994

N-(sulfonyloxy)phthalimides and analogues are potent inactivators of serine proteases.

A series of 2-(sulfonyloxy) and 2-(acyloxy)-1H-isoindole-1,3(2H)-diones and analogous 1H-benz[de]isoquinoline-1,3(2H)-diones was prepared, and their potential to inactivate chymotrypsin was investigated. The N-(sulfonyloxy) and N-(acyloxy)phthalimides were found to be potent inactivators of chymotrypsin and related serine proteinases. For the most active compounds, N-(dansyloxy)phthalimide and N-(tosyloxy)phthalimide, the second-order rate constant of chymotrypsin inactivation was in the range of 250,000 m-1 s-1. N-(Mesyloxy)-phthalimide was the most active compound for inactivation of leukocyte elastase. It was shown that these compounds act as true suicide substrates. Enzyme-catalyzed opening of the heterocyclic ring results in the formation of an acyl-enzyme with attached O-acyl or O-sulfonylhydroxamic acid moiety. Subsequent Lossen rearrangement leads to the formation of a highly reactive isocyanate, which irreversibly modifies the target protease.

Acylation↗
PubMed1983

Hypolipidemic activity of phthalimide derivatives IV: Further chemical modification and investigation of the hypolipidemic activity of N-substituted imides.

A further investigation of N-substituted derivatives of phthalimide for hypolipidemic activity has revealed that the chain length, as well as the type of substitution on the N-alkyl chain of phthalimide is critical for biological activity. In these studies the hypolipidemic activity was not improved by extending the chain length beyond five carbon atoms in the alkyl and alkanoic acid series. Imido nitrogen substituents, other than alkanoic acids, methyl ketones, and alkyl groups, caused a reduction in hypolipidemic activity, e.g., hydroxy, amino, hydroxymethyl, or carbethoxy. Reduction of the keto group in the side chain to an alcohol, as well as forming derivatives of the keto group, did not improve the hypolipidemic activity with the exception of 1-N-phthalimidobutan-3-one semicarbazone. This compound demonstrated improved hypocholesterolemic activity over phthalimide and 1-N-phthalimidobutan-3-one. Substitution of the 3-position of the aromatic moiety of phthalimide with an amino or nitro group, as well as substituting a pyridine or cyclohexyl ring for the phenyl ring, led to the loss of hypolipidemic activity.

Animals↗
PubMed1995

The cytotoxicity of N-Pyridinyl and N-quinolinyl substituted derivatives of phthalimide and succinimide.

The N-pyridinyl and N-quinolinyl substituted derivatives of phthalimides and succinimides demonstrated cytotoxicity against the growth of a number of cultured cell lines. The substituted succinimides were more effective than the unsubstituted succinimide derivative in reducing cell growth. On the other hand, phthalimide demonstrated more potent cytotoxicity than its N-substituted derivatives. Three representative examples N-[2-pyridinyl-1-oxide) methyl] phthalimide 8, 1-[N-2-phthalimidoethyl]-3,4-dihydroiso-quinoline 12, and 1-[N-(2-(1,2,3,4-tetrahydro-2-quinolinyl)] ethylphthalimide 14 were shown to inhibit L1210 leukemia DNA synthesis whereas RNA synthesis was not inhibited at 25-100 uM. All three agents inhibited the activities of DNA polymerase alpha, PRPP-amido transferase, nucleoside kinases, and dihydrofolate reductase. The cellular pool levels of d[GTP], d[CTP], and d[TTP] were reduced after 60 minutes incubation at 100 uM. The DNA molecule itself was not a target of these agents.

Animals↗
PubMed1983

Antihyperlipidemic activity of phthalimide analogues in rodents.

Phthalimide analogues have been shown to effectively lower serum cholesterol and triglyceride levels in rats and mice. The mode of action of these agents was not to suppress the appetite of animals, but rather to reduce the activities of key enzymes in the early synthesis of liver cholesterol and fatty acids in the triglyceride pathway. Phthalimide analogues were effective in accelerating biliary excretion of cholesterol and blocking its absorption from the gut. After 16 days dosing, it was evident that higher levels of lipids were being excreted than in control mice. The major serum lipoprotein fractions were reduced in cholesterol, triglyceride, and neutral lipid content, but not phospholipid content in rats after 14 days of administration.

Animals↗
PubMed1984

Hypolipidemic activity of phthalimide derivatives V: Reduced and hydrolytic products of simple cyclic imides.

A series of cyclic imides and related compounds have previously been shown to possess hypolipidemic activity at the low dose level of 20 mg/kg/d. Hydrolytic and reduced products of the cyclic imides were synthesized and examined to discern if possible metabolic products were the active chemical species of these hypolipidemic agents. Phthalimide proved to be the most active cyclic imide tested. Unfortunately, the new products did not, in general, improve hypolipidemic activity in rodents. The exceptions were piperidine which demonstrated improved hypotriglyceridemic activity, and 3,4,5,6-dibenzohomopiperidin-2-one, which demonstrated improved hypocholesterolemic activity compared to phthalimide.

Animals↗
PubMed1996

Amino acid-derived phthalimide and saccharin derivatives as inhibitors of human leukocyte elastase, cathepsin G, and proteinase 3.

Amino acid-derived phthalimide and saccharin derivatives have been investigated for their inhibitory activity toward the serine proteinases human leukocyte elastase, cathepsin G, and proteinase 3. The saccharin derivatives were found to be effective time-dependent inhibitors of elastase and proteinase 3 (kobs/[I] values ranged between 180 and 3620 M-1 S-1) and showed weak or no inhibition toward cathepsin G. The corresponding phthalimide derivatives were found to be inactive.

Amino Acid Sequence↗
PubMed1995

The Gabriel-Colman rearrangement in biological systems: design, synthesis and biological evaluation of phthalimide and saccharin derivatives as potential mechanism-based inhibitors of human leukocyte elastase, cathepsin G and proteinase 3.

The results of a structure-activity relationship study focusing on the interaction of a series of phthalimide and saccharin derivatives with leukocyte elastase, cathepsin G and proteinase 3 are described. The phthalimide derivatives were found to be inactive while some of the saccharin derivatives were found to be fair inhibitors of these enzymes.

Cathepsin G↗
PubMed1988

The effects of phthalimide and saccharin derivatives on low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptor activity and related enzyme activities.

The hypolipidemic agents, phthalimide, saccharin, o-(N-phthalimido) acetophenone, N-(p-chlorobenzoyl) sulfamate, and o-chlorobenzylsulfonamide affected low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptor activity and lipoprotein degradation. In isolated rat hepatocytes, rat aorta foam cells, and human fibroblasts, LDL receptor activity, which is dependent on apo-B and -E, was inhibited by the drugs in a dose-dependent manner. LDL degradation was accelerated in the hepatocytes, while it was inhibited in aorta cells and fibroblasts. The drugs enhanced HDL receptor activity, dependent on apo-E and -A1, and HDL degradation in the hepatocytes, whereas in fibroblasts and aorta cells HDL receptor binding and degradation were suppressed. In parallel, activities of acyl CoA acyl transferase, sn-glycerol-3-phosphate acyl transferase, and heparin-induced lipoprotein lipase decreased and activities of HMG-CoA reductase and cholesterol oleate-ester hydrolase increased. In fibroblasts the presence of drugs enhanced HDL binding of intracellular cholesterol. In vivo studies demonstrated that phthalimide and saccharin treatment enhanced the clearance of HDL and decreased the clearance of LDL from the serum of rats. The results suggest that the mode of action of the agents is to modulate the lipoprotein receptor and, thereby, the clearance of lipids from peripheral tissue as part of the hypolipidemic activity.

Animals↗