Series Of Phthalimides Research Articles

In vivo Analgesic Activity of New N-arylphthalimides Derivatives in Mice.

A series of phthalimides related to thalidomide have been studied for analgesic activity in the formalin test. The formalin test was performed in mice in a nociceptive pattern to evaluate analgesic activity. In this study, nine derivatives of phthalimides were evaluated in terms of exerting analgesic effects in mice. They exerted significant analgesic effects compared to indomethacin and negative control. These compounds were synthesized and characterized by TLC, followed by IR and H1NMR in the previous studies. Two distinct periods of high licking activity were used to analyze both acute and chronic pain. All compounds were compared with indomethacin and carbamazepine as positive control and vehicle as a negative control. All of the tested compounds exhibited significant analgesic activity in both the first and second phases of the test compared to the control group (DMSO), although they did not show more activity than the reference drug (indomethacin) but were comparable to indomethacin. This information may be useful in the development of a more potent phthalimide as an analgesic agent that acts as a sodium channel blocker and COX inhibitor.

The First Detection of Phthalimides in Sediments as Novel Biomarkers for Photosynthetic Organisms

Abstract We detected a homologous series of phthalimides in organic solvent extracts of Cretaceous to Quaternary sediments. 2-Ethyl-3-methylmaleimide has been found in present-day sediments as a degradation product of chlorophylls; therefore, an authentic sample was heated, affording phthalimide and its homologs as well as homologs of maleimide. The heating products showed a similar molecular distribution of phthalimide and methylphthalimides to those found in the sediments analyzed. These results suggest that the phthalimides found in old sediments are derived from chlorophylls via 2-ethyl-3-methylmaleimide by geochemical transformation.

Efficient Synthesis of 2‐Substituted Phthalimides from Phthalic Acids in One Step

AbstractEfficient procedures for synthesizing 2‐substituted phthalimide (isoindole‐1,3‐dione) analogues starting from phthalic acids have been developed by using experimental design. The phthalimide central fragment frequently appears in biologically active compounds, materials, catalysts, and fluorescent probes, and therefore the development of general, fast, and convenient synthetic methods to this scaffold under neutral, acidic, and basic conditions would be attractive. After an initial screening, the use of acetonitrile, acetic acid, or pyridine in combination with microwave heating proved most promising. Experimental design was applied to these conditions to optimize the time, temperature, and concentration. This strategy has successfully generated synthetic methods that have been used to synthesize a series of phthalimides from phthalic acids and various amines or anilines in excellent yields. The developed methods have proven to be general, fast, convenient, and economic, and thus are expected to have broad utility to efficiently construct novel compounds for future biological and chemical applications.

Synthesis and evaluation of the anxiolytic activity of some phthalimide derivatives in mice model of anxiety.

The aim of the present study was to synthesis a series of phthalimides based on our previous works and examine their anxiolytic properties. Using a three steps process, phthalimides were prepared from the corresponding di-methyl phthalate derivatives. Phthalic anhydride was nitrated to produce 3-nitrophthalic acid. Ring closer of either 3-nitrophthalic acid or di-methyl phthalate with urea were carried out in reflux condition. Final compounds were prepared by base catalyzed condensation of 4-methylbenzoyl chloride, benzoyl chloride and benzyl chloride with the resulting imides. From the tested compounds, only N-benzoyl 3-nitro-phthalimide was shown to produce anxiolytic activity by increasing the number of entries and time spent in open arms at 10 mg/kg.

Photoinduced hydrogen atom abstraction in N-(adamantyl)phthalimides: structure–reactivity study in the solid state

Adamantyl-functionalized phthalimides were synthesized and the probability of intramolecular photochemical hydrogen atom abstraction in the solid state analyzed by X-ray crystallographic analyses. These analyses and solid-state photolyses showed that the parameters determining photochemical reactivity for typical carbonyl compounds in the solid state can also be extended to phthalimides. Only N-(2-adamantyl)phthalimide underwent a solid-state photochemical reaction, which is the first example in the phthalimide series. This reaction is regio- and stereoselective, resulting in an endo-alcohol. On the other hand, the photoreaction of N-(2-adamantyl)phthalimide in solution gives an exo-alcohol as the main product together with an endo-alcohol and a benzazepindione.

2-(3-Hydroxypropyl)isoindoline-1,3-dione: competition among hydrogen-bond acceptors

The title compound, C(11)H(11)NO(3), has two molecules in the asymmetric unit, which differ in the orientation of their side-chain OH groups, allowing them to form intermolecular O-H...O hydrogen bonds to different acceptors. In one case, the acceptor is the OH group of the other molecule, and in the other case it is an imide O=C group. This is the first example in the N-substituted phthalimide series in which independent molecules have different types of acceptor. Molecular-orbital calculations place the greatest negative charge on the OH group.

Synthesis and HIV‐1 Reverse Transcriptase Inhibitory Activity of Non‐Nucleoside Phthalimide Derivatives

AbstractA new type of non‐nucleoside HIV‐1 reverse transcriptase inhibitors in phthalimide series has been synthesized from either the reaction of N‐carboethoxyphthalimide with amines or phthalimide with appropriate alkyl halides. The in vitro inhibitory activity of the synthesized compounds was studied by a radiometric assay at a concentration of 200 µg/mL using poly(rA)·oligo(dT) as a template‐primer and methyl‐[3H]dTTP as a substrate. The three most potent compounds, N‐(m,p‐dihydroxybenzyl)phthalimide (11), N‐[2‐(α‐furyl)ethyl]phthalimide (29) and N‐(5‐methylpyrazin‐2‐ylmethyl)phthalimide (25) exhibited IC50 values of 60.90, 98.10 and 120.75 µg/mL, respectively, lower than IC50 of delavirdine (502.22 µg/mL, using poly(rA)·oligo(dT) as a template‐primer and [3H]dTTP as a substrate).

Exocyclic–Endocyclic N‐Acyliminium Ion Equilibration via an Intramolecular α‐Thioamidoalkylation in the Synthesis of Fused N,S‐Heterocyclic Systems: Some New Parameters

AbstractThe reactivity of N‐[aryl(or alkyl)thio(oxo or seleno)alkylamidals 6 bearing the N‐(CH2)n‐X‐(CH2)m‐Ar functionality towards neat TFA has been examined. Substrates of type 6 give, together with the products 11, 17, 19, and 25 of the “expected” π‐cyclization process, the “unexpected” products 12, 18, and 26 resulting from a new tandem heteroamidoalkylation/isomerization/π‐cyclization. The composition of the final isomeric mixture depends on the temperature of the reaction, with a high selectivity in favor of the “expected” π‐cyclization product 11 as a thermodynamic isomer. Furthermore, the results demonstrate again the relevance of TFA catalysis and support two reaction pathways involving the formation of an aza‐sulfonium cation A as a valuable intermediate which undergoes the π‐cyclization process alone or in tandem with the thiocyclization/isomerization to give the cyclized products cited above. For the latter tandem reaction, we have established clearly that the n value should be equal to 1, the process can be performed independently for both the succinimide and phthalimide series, the reaction depends on the nucleophilicity of the heteroatom, and can be generalized to other heterocycles. Only the role of the benzene substitution has still to be totally elucidated. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Studies on the liquid crystalline behaviour of novel N-alkyl-substituted ester imides

Three new series of N-alkyl-substituted ester imide derivatives, which differ in the polarity of their mesogenic groups; specifically, either cholesteryl, 4′-undecyloxybiphenyl or 4′-cyanobiphenyl, have been synthesized. For the N-alkyl-[4-(cholesteryloxycarbonyl)]phthalimides the chiral nematic N* phase and the monolayer SmA1 phase have been observed up to the dodecyl homologue. The pentadecyl and octadecyl members of this series show only the SmA1 phase. The monolayer smectic A1 phase was also observed for all members of the N-alkyl-4-[(4′-undecyloxybiphenyl-4-yl)oxycarbonyl]phthalimide series while the longer homologues (with n>5) exhibited SmA–SmC dimorphism. In the case of the N-alkyl-4-[(4′-cyanobiphenyl-4-yl)oxycarbonyl]phthalimides, the short homologues exhibited only a nematic phase, while for the butyl homologue in addition to the nematic phase the bilayered SmA2 phase was observed. The smectic phase vanished for the pentyl and hexyl members but reappeared as a partially bilayered smectic Ad phase for the longer homologues.

3D-QSAR studies on phthalimide derivatives as HIV-1 reverse transcriptase inhibitors

:: : novel non-nucleoside HIV-1 reverse transcriptase inhibitors in a phthalimide series were subjected to the three-dimensional quantitative structure-activity relationship (3D QSAR) studies using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best predictive CoMFA model gave cross-validated r 2 (q 2 ) = 0.688, non-cross-validated r 2 = 0.996, included the highest occupied molecular orbital (HOMO) energies in addition to CoMFA fields, and the best predictive CoMSIA model has q 2 = 0.629, non-cross-validated r 2 = 0.994, included steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. A test set of 12 compounds was used to determine the predictive value of the models. The calculated (predicted) and experimental inhibitory activities were well correlated. The analysis of the 3D contour maps from both CoMFA and CoMSIA models offer important structural insight into designing novel and more active compounds prior to their synthesis.

Photochemistry of Phthalimides: Decarboxylation, Addition, Macrocyclization and Deprotection

AbstractFor Abstract see ChemInform Abstract in Full Text.

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-methylpheryl)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.

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.

Reactivity Optimization of Prevulcanization Inhibitors

Abstract A series of phthalimide-based prevulcanization inhibitors has been used to probe the relationship between MBT reactivity and inhibitor performance efficiency in NR accelerated with TBBS. Based on these results, there appears to be a reactivity window for best performance. For the phthalimide series, it occurs with secondary alkyl mercaptans. Inhibitors with MBT reactivity below the optimum are less effective because they do not compete with the accelerator for the autocatalyst. The activity also falls off at higher reactivities. There are two explanations for this behavior. First, as proposed by others, the very reactive inhibitors may not completely survive mixing and precuring, so that some of the inhibitor is lost to unproductive side reactions. Over and above this effect, the performance declines because the MBT is trapped less securely when the BtSSR is derived from a more reactive mercaptan. Although other leaving groups were not evaluated in this work, it is clear that reactivity optimization can be achieved with any leaving group, L, by proper selection of -SR. For example, in the work of Morita and Sullivan with thioketal type prevulcanization inhibitors, it was demonstrated that primary alkyl and aromatic mercaptans were required to achieve optimum inhibitor activity.