N-substituted Phthalimides Research Articles

Photolysis and Photodegradation of N-Substituted Phthalimides with a Cymantrenyl Moiety

Photolysis and Photodegradation of N-Substituted Phthalimides with a Cymantrenyl Moiety

Anti-oxidant and antibacterial activities of novel N-sulfonylphtalimide in an ovalbumin-induced inflammation in Wistar rats.

Phthalimide and N-substituted phthalimide have a special structure that helps them to be pharmaceutically useful and biologically active. In this study, we investigated the antioxidant, anti-inflammatory and antibacterial effects of a synthetic phthalimide-containing derivative in an experimental asthma model. In vitro determination of antioxidant and chelating activity was carried out by spectrophotometric methods. The in vivo antioxidant activity was carried out in Wistar rats sensitized to ovalbumin in the experimental model of asthma. Our results reveal that that the synthesized N-sulfonylphthalimide molecule has a scavenging capacity against the free radical 2,2-diphenyl-1-picryl-hydrazyl (DPPH•) and a chelating activity on ferrous ions and revealed its protective capacity against altered markers of oxidative stress in the experimental asthma model. All the previous results were confirmed by the result of the histopathological study of the liver. Moreover, neo-synthesized N-sulfonylphthalimide 2 showed antibacterial activity against Gram-positive and Gram-negative bacteria with interesting MIC values. Finally, our study highlights the anti-inflammatory, anti-asthmatic and antibacterial effects of the N-sulfonylphthalimide molecule, which could potentially be a drug of choice in asthmatic pathology, especially during bacterial superinfections in the respiratory tract.

Antifungal, anti-biofilm, and anti-hyphal properties of N-substituted phthalimide derivatives against Candida species.

Candida species comprise a ubiquitous pathogenic fungal genus responsible for causing candidiasis. They are one of the primary causatives of several mucosal and systemic infections in humans and can survive in various environments. In this study, we investigated the antifungal, anti-biofilm, and anti-hyphal effects of six N-substituted phthalimides against three Candida species. Of the derivatives, N-butylphthalimide (NBP) was the most potent, with a minimum inhibitory concentration (MIC) of 100 µg/ml and which dose-dependently inhibited biofilm at sub-inhibitory concentrations (10-50 µg/ml) in both the fluconazole-resistant and fluconazole-sensitive Candida albicans and Candida parapsilosis. NBP also effectively inhibited biofilm formation in other pathogens including uropathogenic Escherichia coli, Staphylococcus epidermidis, Staphylococcus aureus, and Vibrio parahaemolyticus, along with the polymicrobial biofilms of S. epidermidis and C. albicans. NBP markedly inhibited the hyphal formation and cell aggregation of C. albicans and altered its colony morphology in a dose-dependent manner. Gene expression analysis showed that NBP significantly downregulated the expression of important hyphal- and biofilm-associated genes, i.e., ECE1, HWP1, and UME6, upon treatment. NBP also exhibited mild toxicity at concentrations ranging from 2 to 20 µg/ml in a nematode model. Therefore, this study suggests that NBP has anti-biofilm and antifungal potential against various Candida strains.

Salicylaldehyde as an SET-HAT Bifunctional Photocatalyst for the Intermolecular Transalkylation of Phthalimide.

Salicylaldehyde works as an efficient photocatalyst for the intermolecular transalkylation of phthalimide. The well-designed dimethyl N-hydroxyphthalimide ester proves to be a good alkylation reagent. It inhibits the competing intramolecular alkylation of alkylating reagent, enabling the site-specific synthesis of N-substituted phthalimide.

Thermodynamic and Theoretical Studies of some N-substituted phthalimides Derivatives

N,N’-(biphenyl)bisphthalimide and N-(4’-amino __ biphenyl)phthalimide were chosen in this study to compare the stabilitytheoretically by density function theory (DFT) using B3LYP/6-31Gmethod, the electronic properties of these imides indicate that compound(N,N’-(biphenyl)bisphthalimide) is more stable than the compound (N-(4’-aminobiphenyl) phthalimide) by (-0.8422 eV or -19.4215 Keal.mo!'')depending on the values of HOMO, synthesis _ reaction of imide isspontaneous and endothermic at temperature 150°C according to the valuesof A,S, A,G and A,H thermodynamically.INTRODUCTION Imides are organic compounds for N-monoacy] derivatives of amidewhich may be open or cyclic chain. Cyclic imide constitute an importantclass of compounds possessing bis-amide linkage with common nitrogen.Imide very important molecules because their activity as antibacterial,antifungal, anti nociceptive, anticonvulsant and antitumor!, They havebeen useful building blocks in the synthesis of natural products’! and otherheterocycles as well!*!, Their ability to cross biological membranes in-vivo,due to their hydrophobicity is well established'“!,The preparation of imideshas received considerable attention during recent year A number ofmethods such as acylation of amides with acyl chlorides, anhydrides andcarboxylic esters or acids), amino carbonylation of aryl bromides'*! havebeen reported for the preparation of acyclic imides.COMPUTATIONAL METHODS Molecular geometries of the all molecules were fully optimized withthe hybrid density functional theory (DFT) B3LYP method!”"'"! using the6-31G basis set!!?!3! by means of the Gaussian 09, revision A.02!"4! usedfor all geometry optimizitions, thermodynamic functions at conditions

Synthesis of N-substituted phthalimides via Pd-catalyzed [4+1] cycloaddition reaction.

A novel Pd-catalyzed assembly of N-substituted phthalimides by merging of [4+1] cycloaddition and difluorocarbene transfer carbonylation from 2-iodo-N-phenylbenzamides and difluorocarbene precursors is disclosed. Difluorocarbene acts as a carbonyl source and simultaneously forms one C-C bond, one C-N bond and one CO bond to produce N-substituted phthalimides in high yields.

Synthesis, investigation of the cholinesterase inhibitory activities and in silico studies of some novel N-substituted phthalimide derivatives

Synthesis, investigation of the cholinesterase inhibitory activities and in silico studies of some novel N-substituted phthalimide derivatives

Phthaloylation of amines, hydrazines, and hydrazides by N-substituted phthalimides using recyclable sulfated polyborate

An efficient, fast, and environmentally gentle protocol for phthaloylation of amines, hydrazines and hydrazides via transamidation is described. The current research focuses on the phthaloylation of alicyclic, aliphatic, aromatic, heterocyclic amines, hydrazines, and hydrazides. Reaction with N-substituted phthalimides was completed in about 30 minutes at 70 °C in DMSO as a solvent, resulting in higher yield of products, ease of workup, and recyclability of catalyst. In addition to this, transamidation of cinnamamide and benzamide was also successfully achieved.

Adamantane-Functionalized Phthalimide Scaffold: Pathways to Supramolecular Interactions and Drug Discovery

Herein, the synthesis of a novel adamantanyl-functionalized phthalimide scaffold is demonstrated. The novel compound could be used as a precursor for various synthetic pathways owing to the generic use of adamantane substituents as the driving force for supramolecular interactions with macrocycles and N-substituted phthalimide derivatives as a core structure in numerous drugs. The adamantanyl-functionalized phthalimide scaffold contains bromide groups on the C4 and C5 positions of the benzene ring, effectively allowing further facile modifications of the scaffold. The structure was fully characterized including single-crystal X-ray crystallography. The crystal structure shows an adamantane moiety at an angle of 115.57(7)° to the phthalimide core, hence sterically freeing the adamantane unit for host–guest interactions.

Enantiomeric N-substituted phthalimides with excitatory amino acids protect zebrafish larvae against PTZ-induced seizures

Epilepsy is a chronic neurological disease with high prevalence and adverse impacts on the quality of life of patients and caregivers. Up to one-third of individuals with epilepsy do not respond to current pharmacotherapy, underscoring the importance of identifying new molecules for epilepsy control. Thalidomide, the first synthetized phthalimide, is a neuroactive molecule with anti-seizure drug properties. The phthalimide group has been studied in some N-phthaloyl amino acids due to its pharmacological properties. Here we examine enantiomers of phthaloyl aspartate (R and S) and phthaloyl glutamate (R and S) for anti-seizure effects using zebrafish as a model. The zebrafish model is rapidly growing in use as a preclinical screening tool for drug discovery in epilepsy. Pentylenetetrazol (PTZ) exposure was used to produce convulsive behavior in 7- and 10-days post-fertilization (dpf) zebrafish larvae; these ages correspond to before and after the blood-brain-barrier (BBB) is fully developed. Larvae were pre-treated for 60 min with: control, valproic acid sodium salt (SVP) 3 mM, or one of two concentrations of N-phthaloyl-R-glutamic acid (R-TGLU; 100, 316 μM) prior to PTZ addition. R-TGLU modified the locomotor phenotype and protected against PTZ in 7 and 10 dpf larvae at 316 μM, suggesting it crossed the BBB. We next tested the per se and anticonvulsant effect of the glutamate and aspartate phthalimides were tested at 237.1 and 316 μM concentration in 10dpf zebrafish. The four tested molecules produced an anticonvulsant effect at 237.1 μM concentration, however the behavioral changes that they induce suggest that they might act by different mechanisms.

Synthesis of novel isoindolone derivatives via cascade reactions. Contrasting diastereoselectivity under solution-phase vis-a-vis solvent-free ball-milling reaction conditions

The highly diastereoselective synthesis, crystallographic analysis, and full characterization of several novel heterocycle-fused isoindolones is described. The synthetic strategy involves a cascade Michael/aldol-like cyclization reaction between N-substituted phthalimides rac-1 or 2 and several α,β-unsaturated electrophiles to afford the tricyclic systems pyrrolo[2,1- a]isoindolone and tetrahydropyrido[2,1-a]isoindolone. This synthetic strategy offers a convenient alternative to existing procedures for the preparation of isoindolone derivatives fused to five- and six-membered rings. X-ray crystallographic analysis allowed the determination of relative configurations and revealed that the synthesized compounds exhibit significant structural distortion, especially in the five membered rings. Relevantly, the diastereomeric distribution of products depends substantially on whether the cascade reaction is carried out under solution vis-a-vis solvent-free conditions.

Palladium Catalyzed Regioselective Synthesis of Substituted Biaryl Amides through Decarbonylative Arylation of Phthalimides.

The Pd(OAc)2 catalyzed cross-coupling of N-substituted phthalimides with aryl halide provides a single step direct access of a wide range of synthetically appealing ortho-substituted biarylamides in high yields through unique carbonyl (CO) replacement. The reaction proceeds through a ligand-free condition and is well tolerant to the diverse functionality of both imide and halide units. The reaction negates any requirement of organometallic reagent and needs a shorter reaction time and comparatively lower temperature as required for previously reported decarbonylative processes.

Neuropharmacological Screening of Chiral and Non-chiral Phthalimide- Containing Compounds in Mice: in vivo and in silico Experiments.

Thalidomide, the first synthesized phthalimide, has demonstrated sedative- hypnotic and antiepileptic effects on the central nervous system. N-substituted phthalimides have an interesting chemical structure that confers important biological properties. Non-chiral (ortho and para bis-isoindoline-1,3-dione, phthaloylglycine) and chiral phthalimides (N-substituted with aspartate or glutamate) were synthesized and the sedative, anxiolytic and anticonvulsant effects were tested. Homology modeling and molecular docking were employed to predict recognition of the analogues by hNMDA and mGlu receptors. The neuropharmacological activity was tested with the open field test and elevated plus maze (EPM). The compounds were tested in mouse models of acute convulsions induced either by pentylenetetrazol (PTZ; 90 mg/kg) or 4-aminopyridine (4-AP; 10 mg/kg). The ortho and para non-chiral compounds at 562.3 and 316 mg/kg, respectively, decreased locomotor activity. Contrarily, the chiral compounds produced excitatory effects. Increased locomotor activity was found with S-TGLU and R-TGLU at 100, 316 and 562.3 mg/kg, and S-TASP at 316 and 562.3 mg/kg. These molecules showed no activity in the EPM test or PTZ model. In the 4-AP model, however, S-TGLU (237.1, 316 and 421.7 mg/kg) as well as S-TASP and R-TASP (316 mg/kg) lowered the convulsive and death rate. The chiral compounds exhibited a non-competitive NMDAR antagonist profile and the non-chiral molecules possessed selective sedative properties. The NMDAR exhibited stereoselectivity for S-TGLU while it is not a preference for the aspartic derivatives. The results appear to be supported by the in silico studies, which evidenced a high affinity of phthalimides for the hNMDAR and mGluR type 1.

Synthesis of Phthalimides: A New Entry via TBAI-Catalyzed Intramolecular Cyclization of 2-(Hydroxymethyl)benzamides

Herein we report an unprecedented metal-free TBAI/TBHP mediated C–N bond formation via intramolecular cyclization of 2-(hydroxymethyl)benzamides to furnish N-substituted phthalimides in excellent yields.

Synthesis, molecular docking and DNA binding studies of phthalimide-based copper(II) complex: In vitro antibacterial, hemolytic and antioxidant assessment

In the present research work, we prepared N-substituted phthalimide, 2-(-(2-(2-(2-(1,3-dioxoisoindoline-2-yl-ethylamino)ethylamino)ethyl)isoindoline-1,3-dione (DEEI) and its copper(II) complex. The ligand (DEEI) and its Cu(II) complex were structurally identified using absorption, FTIR, NMR, electron spin resonance, X-ray diffraction spectral studies, thermogravimetric and elemental analyses. The electronic spectrum and magnetic moment value proposed that Cu(II) complex has square planar geometry. The DNA interaction ability of the ligand (DEEI) and Cu(II) complex was studied by means of absorption and fluorescence spectrophotometer, viscosity measurements, cyclic voltammetery, and circular dichroism methods. The extent of DNA binding (Kb) with Calf thymus (Ct-DNA) follows the order of Cu(II) complex (1.11 × 106 M−1) > DEEI (1.0 × 105 M−1), indicating that Cu(II) complex interact with Ct-DNA through groove binding mode and more sturdily than ligand (DEEI). Interestingly, in silico predictions were corroborated with in vitro DNA binding studies. The antibacterial evaluation of these compounds was screened against a panel of bacterial strains Pseudomonas aeruginosa (MTCC 2453), Salmonella enterica (MTCC 3224), Streptococcus pneumoniae (MTCC 655), Enterococcus faecalis (MTCC 439), Klebsiella pneumonia and Escherichia coli (ATCC 25922). The results showed that the copper(II) complex has significant antibacterial potential (IC50 = 0.0019 μg/mL) against Salmonella enteric comparable with ligand (DEEI) and standard drug ciprofloxacin. Growth curve study of Cu(II) complex against only three bacterial strains S. enterica, E. faecalis and S. pneumoniae showed its bactericidal nature. Cu(II) complex showed less than 2% hemolysis on human RBCs indicating its non toxic nature. The results of antioxidant assay demonstrated that scavenging activity of Cu(II) complex is higher as compared to ligand and ascorbic acid as standard.

Structure-based design, synthesis, PPAR-γ activation, and molecular docking of N-substituted phthalimides

N-substituted phthalimides showed peroxisome proliferator-activated receptors-γ activation in rat liver epithelial Ac2F cells in our previous study. In order to explore better peroxisome proliferator-activated receptors-γ agonists, new N-substituted phthalimide derivatives were designed and synthesized based on a pharmacophore study of natural peroxisome proliferator-activated receptors-γ agonist paecilocin A and synthetic leads. Peroxisome proliferator-activated receptors-γ activation by the new derivatives was evaluated using rat liver epithelial Ac2F cells at a concentration of 10 μM (same as previous study). All the new derivatives showed comparable or better activities than that of rosiglitazone, in which 3-hydroxy-N-(p-methoxy-phenethyl) phthalimide (compound 6) appeared as the best. Molecular docking suggested that the free hydroxyl group on the phthalimide head, a proper hydrophobic tail including a phenyl linker, were beneficial for peroxisome proliferator-activated receptors-γ activation. These N-substituted phthalimide derivatives are valuable as scaffolds for new peroxisome proliferator-activated receptors-γ agonists.

Synthesis of Amides and Phthalimides via a Palladium Catalyzed Aminocarbonylation of Aryl Halides with Formic Acid and Carbodiimides.

A novel method for the preparation of amides and phthalimides has been developed. The process involves a palladium catalyzed aminocarbonylation of an aryl halide, using a carbodiimide and formic acid as the carbonyl source. Experimental data suggest that the mechanistic pathway for this process involves in-situ generation of carbon monoxide from the reaction of formic acid with a carbodiimide in the presence of a palladium catalyst. The method can be used to produce a variety of amides and N-substituted phthalimides efficiently.

An efficient synthesis of N-substituted phthalimides using SiO2-tpy-Nb as heterogeneous and reusable catalyst

A novel and efficient heterogeneous catalyst SiO2-tpy-Nb was developed, and its application in the preparation of N-substituted phthalimides from o-phthalic acids or anhydrides with amines provides the desired products in good to excellent yields. The catalyst was stable and recoverable for eight consecutive cycles without a significant loss in its activity. Furthermore, the catalyst is applicable in continuous flow which indicates its potential utilization in industrialization.

ChemInform Abstract: Transition‐Metal‐Catalyzed Direct Addition of Aryl C—H Bonds to Unsaturated Electrophiles

AbstractReview: [37 refs.

Phthalimide-derived strigolactone mimics as germinating agents for seeds of parasitic weeds.

Broomrapes attack important crops, cause severe yield losses and are difficult to eliminate because their seed bank is virtually indestructible. In the absence of a host, the induction of seed germination leads to inevitable death due to nutrient starvation. Synthetic analogues of germination-inducing factors may constitute a cheap and feasible strategy to control the seed bank. These compounds should be easy and cheap to synthesise, as this will allow their mass production. The aim of this work is to obtain new synthethic germinating agents. Nineteen N-substituted phthalimides containing a butenolide ring and different substituents in the aromatic ring were synthesised. The synthesis started with commercially available phthalimides. The complete collection was assayed against the parasitic weeds Orobanche minor, O. cumana, Phelipanche ramosa and P. aegyptiaca, with the synthetic strigolactone analogue GR24 used as a positive control. These compounds offered low EC50 values: O. cumana 38.3 μM, O. minor 3.77 μM, P. aegyptiaca 1.35 μM and P. ramosa 1.49 μM. The synthesis was carried out in a few steps and provided the target compounds in good yields. The compounds tested showed great selectivity, and low EC50 values were obtained for structures that were simpler than GR24. © 2016 Society of Chemical Industry.