Succinimide Derivatives Research Articles

Phosphine-Catalyzed [3 + 4] Annulations of Salicylaldehyde Schiff Bases with α-Substituted Allenes: Construction of Functionalized Benzoxepine Fused Succinimide Derivatives.

Herein we reported a novel strategy for constructing benzoxepine fused succinimide derivatives via a phosphine-catalyzed [3 + 4] cyclization of α-substituted allenes and salicylaldehyde Schiff bases. This methodology serves as a conduit for the construction of benzoxepine derivatives in good yields under mild conditions by an unprecedented mode involving the β'-carbon of allenes. Density functional theory calculations were conducted to study the possible mechanism. Moreover, this class of compounds exhibited the potential ability of cytotoxicity toward cancer cells.

Mn(I)-Catalyzed Site-Selective C-H Activation: Unlocking Access to 3-Arylated Succinimides from 2-Arylpyridines and Maleimides.

An efficient and cost-effective Mn(I)-catalyzed site-selective C-H activation of 2-arylpyridines with maleimides has been described. This approach facilitates the synthesis of 3-arylated succinimide derivatives with high site selectivity, chemoselectivity, catalytic efficiency, and outstanding tolerance to numerous functional groups. The practicality of this approach is further evidenced by its successful application in large-scale reactions and the conversion of the synthesized succinimide derivatives into other valuable compounds.

Ruthenium (II)‐Catalysed Regioselective C6 Alkylation of Indoles with Maleimides

Ruthenium (II)‐catalysed regioselective C6 alkylation of indole‐7‐carboxamides with maleimide has been described. Electronically diverse maleimides reacted with various indoles to furnish corresponding C6 substituted succinimide derivatives of indoles with 46‐89% yields. The reaction shows broad functional group tolerance. The synthetic utility of the reaction has been demonstrated through the conversion of the obtained product to the corresponding hexahydropyridazinyl derivative. We also studied the kinetics of the reaction through intermolecular competitive experiments with electronically distinct indole‐7‐carboxamides.

Phosphine-Catalyzed Stereospecific and Enantioselective Desymmetrizative [3+2] Cycloaddition of MBH Carbonates and N-(2-tert-Butylphenyl)maleimides.

Herein, we report an l-valine-derived amide phosphine-catalyzed [3+2] cyclization of MBH carbonates and N-(2-tert-butylphenyl)maleimides via asymmetric desymmetrization. Bicyclic N-aryl succinimide derivatives bearing three continuous chiral centers with a remote C-N atropisomeric chirality were constructed stereospecifically and enantioselectively. A wide variety of MBH carbonates could be employed in this process to deliver highly optically pure succinimide derivatives in moderate to excellent yields.

Succinimide Derivatives as Acetylcholinesterase Inhibitors-In Silico and In Vitro Studies.

We studied the effect of succinimide derivatives on acetylcholinesterase activity due to the interest in compounds that influence this enzyme's activity, which could help treat memory issues more effectively. The following parameters were established for this purpose based on kinetic investigations of the enzyme in the presence of succinimide derivatives: the half-maximal inhibitory concentration, the maximum rate, the inhibition constant, and the Michaelis-Menten constant. Furthermore, computational analyses were performed to determine the energy required for succinimide derivatives to dock with the enzyme's active site. The outcomes acquired in this manner demonstrated that all compounds inhibited acetylcholinesterase in a competitive manner. The values of the docking energy parameters corroborated the kinetic parameter values, which indicated discernible, albeit slight, variations in the inhibitory intensity among the various derivatives.

Study of pH-Dependent Kinetics of Filgrastim Pegylation with Succinimide Derivatives of Poly(Ethylene Glycol) and Comparison of the Properties of Pegylated Forms Obtained Under Various Conditions

Study of pH-Dependent Kinetics of Filgrastim Pegylation with Succinimide Derivatives of Poly(Ethylene Glycol) and Comparison of the Properties of Pegylated Forms Obtained Under Various Conditions

Cyclic Imides Derivatives: A Potential Scaffold For The Synthesis Of Anticonvulsant Agents

Cyclic non-aromatic nitrogen heterocycles such as phthalimides, maleimides, and succinimides are an intriguing class of compounds with an immense range of biological activities such as anti-convulsant, anti-inflammatory, anti-microbial, analgesic, and hypolipidemic activities, as well as numerous pharmaceutical uses. Phthalimide, maleimide, and succinimide have an imide functional group and can be considered nitrogen analogs of anhydrides. The imide ring and general structure of CO-N(R)-CO found in cyclic imides, including phthalimides, maleimides, succinimides, and their derivatives, impart hydrophobicity and neutral properties onto the respective derivatives. The unsubstituted cyclic imide is a crucial feature that has been shown to retain considerable biological activity. In this article, we intend to investigate several phthalimides, maleimides, and succinimide derivatives, their chemistry, structural activity relationship (SAR), and anticonvulsant activity, considering their immense biological activities.

Visible-Light-Initiated Catalyst-Free Radical Annulation Reactions of 1,6-Enynes and Aryl Sulfonyl Bromide to Assemble Sulfonation/Bromination Succinimide Derivatives.

In the present study, the environment-friendly visible-light-promoted strategy is used to perform an efficient, simple, and straightforward photocatalytic succinimide derivative synthesis from the reaction of 1,6-enynes and aryl sulfonyl bromide at room temperature under air ambient conditions. This method features mild conditions, broad substrate scope, high yields, and excellent configurational selectivity. In addition, all the atoms of the substrates involved in the reaction converge in the product structures, showing a high atomic economy. Moreover, the most important characteristic of this study is that no photocatalyst and additives are used, while the key factor that triggers the reaction is visible light, indicating that this study has an important practical value.

Upcycling poly(succinates) with amines to N-substituted succinimides over succinimide anion-based ionic liquids

The chemical transformation of waste polymers into value-added chemicals is of significance for circular economy and sustainable development. Herein, we report upcycling poly(succinates) (PSS) with amines into N-substituted succinimides over succinimide anion-based ionic liquids (ILs, e.g, 1,8-diazabicyclo[5.4.0]undec-7-ene succinimide, [HDBU][Suc]). Assisted with H2O, [HDBU][Suc]) showed the best performance, which could achieve complete transformation of a series of PSS into succinimide derivatives and corresponding diols under mild and metal-free conditions. Mechanism investigation indicates that the cation-anion confined hydrogen-bonding interactions among IL, H2O, ester group, and amino/amide groups, strengthens nucleophilicity of the N atoms in amino/amide groups, and improves electrophilicity of carbonyl C atom in ester group. The attack of the amino/amide N atom on carbonyl C of ester group results in cleavage of carbonyl C-O bond in polyester and formation of amide group. This strategy is also effective for aminolysis of poly(trimethylene glutarate) to glutarimides, and poly(1,4-butylene adipate) to caprolactone diimides.

In situ Raman spectral observation of succinimide intermediates in amyloid fibrillation kinetics

Succinimide intermediates play the crucial role in the nucleation process for protein amyloid fibril formation, as they can usually induce a non-native conformation in a fraction of soluble proteins to render amyloidogenicity and neurotoxicity. Thus, in situ detection of succinimide intermediates during amyloid fibrillation kinetics is of considerable importance, albeit challenging, because these succinimides are generally unstable in physiological conditions. Here, we found an in situ Raman spectral fingerprint to trace the succinimide intermediates in amyloid fibril formation, wherein the carbonyl symmetric stretching of cyclic imide in the succinimide derivative is located at ca. 1790 cm−1. Using its intensity as an indicator of succinimide intermediates, we have in situ detected and unravelled the role of succinimide intermediates during the oligomer formation from the Bz-Asp-Gly-NH2 dipeptide or the amyloid fibrillation kinetics of lysozyme with thermal/acid treatment.

Blue Light‐Promoted Synthesis of Thiochromenopyrroledione Derivatives via Titanium Dioxide‐Catalyzed Dual Carbon–Carbon Bond Formation with Thioanisole and Maleimide Derivatives

AbstractUnder anaerobic conditions, thioanisole derivatives bearing a thiomethyl group participated in dual carbon‐carbon bond‐forming reactions with maleimide derivatives in the presence of titanium dioxide. Blue light irradiation facilitated these reactions, producing thiochromenopyrroledione derivatives and nearly equimolar quantities of succinimide derivatives. Specifically, a thiochromenopyrroledione derivative formed from thioanisole and N‐benzylmaleimide was achieved with a 43% yield after 12 hours of blue light exposure (>420 nm), approaching its theoretical maximum yield of 50%. Without titanium dioxide, the reaction remained dormant. Our investigations with five varieties of 4‐substituted thioanisoles and four N‐substituted maleimides as precursors resulted in the synthesis of 20 distinct thiochromenopyrroledione derivatives with moderate to high yields. From observed substituent effects, we postulate that this reaction proceeds through a charge transfer from thioanisole to the conduction band of titanium dioxide during blue light irradiation, initiating the one‐electron oxidation of thioanisole and subsequent generation of α‐thioalkyl radicals via deprotonation.

Exploration of ketone derivatives of succinimide for their antidiabetic potential: In vitro and in vivo approaches

Abstract Diabetes mellitus (DM) is one of the most challenging diseases among all the other diseases in the recent era, and it is a life-threatening disorder. The best enzymes to target for treating DM are α-glucosidase and α-amylase. For this purpose, we explored numerous succinimides with ketone functionalities. First, we explored these compounds for their in vitro analysis. Compounds 1 and 4 exhibited excellent inhibition of both enzymes in in vitro studies. These compounds displayed excellent activity with IC50 values of 3.69 and 1.526 µg·mL−1 against the α-glucosidase enzyme. In the α-amylase inhibitory assay, compound 1 has shown excellent potential with an IC50 value of 1.07 µg·mL−1 and compound 4 with an IC50 value of 0.115 µg·mL−1. Based on the in vitro analysis, the potent compounds were further subjected to their in vivo analysis. Before the in vivo analysis, the toxicity profile was checked, and it was confirmed that the compounds were safe at 1,500 µg·kg−1. Then, these compounds were subjected for their in vivo anti-diabetic potential in a mouse model of diabetes. Various concentrations of compounds 1 and 4 were explored by in vivo analysis using glibenclamide as a standard drug. The blood glucose level of the tested and control groups was measured at 0 to 15 days accordingly. Similarly, we also explored compounds 1 and 4 for the oral glucose tolerance test at 0–120 min using glibenclamide as the standard drug. Hence, the succinimide having ketone moiety displayed excellent potential against diabetes.

Mechanochemical synthesis and anticonvulsant activity of 3-aminopyrrolidine-2,5-dione derivatives

A series of 3-aminopyrrolidine-2,5-dione derivatives was synthesized and tested for anticonvulsant activity. Succinimide derivatives were obtained from a simple solvent-based reaction and a mechanochemical aza-Michael reaction of maleimide or its N-substituted derivatives with selected amines. The structure of the compounds was confirmed by spectroscopic methods (NMR, FT-IR, HPLC, ESI-MS, EA and XRD for four compounds). The cytotoxic activity of the succinimide derivatives was evaluated using HepG2 cells for hepatocytotoxicity and SH-SY5Y cells for neurocytotoxicity. None of the studied compounds showed hepatocytotoxicity and two showed neurocytotoxicity. Initial anticonvulsant screening was performed in mice using the psychomotor seizure test (6 Hz, 32 mA). The selected compounds were evaluated in the following acute models of epilepsy: the maximal electroshock test, psychomotor seizure test (6 Hz, 44 mA), subcutaneous pentylenetetrazole seizure test, and acute neurotoxicity (rotarod test). The most active compound 3-((4-chlorophenyl)amino)pyrrolidine-2,5-dione revealed antiseizure activity in all seizure models (including pharmacoresistant seizures) and showed better median effective doses (ED50) and protective index values than the reference compound, ethosuximide. Furthermore, 3-(benzylamino)pyrrolidine-2,5-dione and 3-(phenylamino)pyrrolidine-2,5-dione exhibited antiseizure activity in the 6 Hz and MES tests, and 3-(butylamino)−1-phenylpyrrolidine-2,5-dione and 3-(benzylamino)−1-phenylpyrrolidine-2,5-dione exhibited antiseizure activity in the 6 Hz test. All active compounds demonstrated low in vivo neurotoxicity in the rotarod test and yielded favourable protective indices.

Silver-catalyzed radical bisphosphonation reaction of maleimides with diarylphosphine oxides

A silver-catalyzed bisphosphonate reaction of substituted maleimides with various diarylphosphine oxides was developed. This methodology provided an efficient strategy to prepare phosphorus–containing succinimide derivatives with satisfactory yields. The reaction exhibited mild reaction conditions and good functional group compatibilities. The radical species induced pathway was also demonstrated by mechanistic studies.

Exploration of Succinimide Derivative as a Multi-Target, Anti-Diabetic Agent: In Vitro and In Vivo Approaches

Diabetes mellitus (DM) is counted among one of the leading challenges in the recent era, and it is a life-threatening disorder. Compound 4-hydroxy 3-methoxy phenylacetone (compound 1) was previously isolated from Polygonum aviculare. This compound was reacted with N-benzylmaleimide to synthesize the targeted compound 3. The purpose of this research is to exhibit our developed compound 3's ability to concurrently inhibit many targets that are responsible for hyperglycemia. Compound 3 was capable of inhibiting α-amylase, α-glucosidase, and protein tyrosine phosphatase 1 B. Even so, outstanding in vitro inhibition was shown by the compound against dipeptidyl peptidase-4 (DPP-4) with an IC50 value of 0.07 µM. Additionally, by using DPPH in the antioxidant activity, it exhibited good antioxidant potential. Similarly, in the in vivo activity, the experimental mice proved to be safe by treatment with compound 3. After 21 days of examination, the compound 3 activity pattern was found to be effective in experimental mice. Compound 3 decreased the excess peak of total triglycerides, total cholesterol, AST, ALT, ALP, LDL, BUN, and creatinine in the STZ-induced diabetic mice. Likewise, the histopathology of the kidneys, liver, and pancreas of the treated animals was also evaluated. Overall, the succinimde moiety, such as compound 3, can affect several targets simultaneously, and, finally, we were successful in synthesizing a multi-targeted preclinical therapy.

Phosphine-catalyzed Rauhut-Currier reaction of γ-alkyl allenoate and subsequent trapping using the Diels-Alder reaction.

We have disclosed a Rauhut-Currier reaction of γ-alkyl-substituted allenoate, catalyzed by L-valine-derived amide phosphine, to form trisubstitued allenoate, which was trapped by maleimide or DMAD via the Diels-Alder reaction. Exo-bicyclic succinimide derivatives including three continuous stereocenters with an exo-carbon-carbon double bound were constructed in up to quantitative yields with high stereospecificity.

Predicting percutaneous permeation for new succinimide derivatives by in vitro and in silico models

Percutaneous permeation of twenty-four newly synthesized succinimide derivatives was evaluated using parallel artificial membrane permeability assay (PAMPA) with 70% silicone oil and 30% isopropyl myristate. Different online tools were applied for in silico predicting of their skin permeability. According to the in silico estimation of the transdermal permeation, all compounds are expected to have relatively good ability to permeate the skin, at pH=6. However, for two compounds containing carboxylic groups, the concentration in the acceptor compartment was undetectable indicating limited permeation at pH=7.4. Statistically significant association was found between in silico predicted logKp values by the PreADMET and SwissADME online tools and the percutaneous permeability estimated from the experimental results using the artificial membranes (adj. r2 = 0.371, p = 0.00158 and adj. r2=0.232, p = 0.0135, respectively). The association between permeation through artificial membranes and the calculated logP data was also statistically significant. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) took into account in silico logKp and calculated logP data. The ranking of the lipophilicity and skin permeability parameters was conducted with sum of ranking differences (SRD) analysis which was validated. Based on the obtained results, it is predicted that lipophilicity is a pivotal physico-chemical parameter of the passive permeation of succinimide derivatives through hydrophobic barriers such as the skin.

Facile synthesis, pharmacological and In silico analysis of succinimide derivatives: An approach towards drug discovery

The hybrid heterocyclic scaffolds possess extensive medicinal values and significant pharmaceutical usage. A series of N-substituted-2,5-dioxopyrrolidine carboxamides/carbothioamides have been synthesized under aqueous conditions using clean microwave irradiation technology. The quantum chemical data and chemical reactivity parameters of the title compounds have been derived by DFT execution. The synthesized compounds have been screened for In vitro biological evaluation to ascertain their antimicrobial potential and radical scavenging ability. The promising antifungal activity of the synthesized compounds is further explored with molecular docking simulation revealing favorable binding interactions and good docking score against glucosamine-6-phosphate synthase (GlcN-6-P, PDB: 1JXA). The pharmacokinetics and drug analogy of the title compounds have been deduced by ADMET prediction and drug likeliness with the ‘Lipinski rule of 5′. The encouraging bioavailability plots permit the oral ingestion of the synthesized drug candidates. In vitro and In silico inspection of the lead molecules manifest them as potential antifungal agents with an appreciable antiradical ability that could be exploited in the future as a therapeutic alternate in fungal skin infections as well as in opportunistic fungal infections in immunocompromised patients.

Synthesis, Molecular Docking, and Preclinical Evaluation of a New Succinimide Derivative for Cardioprotective, Hepatoprotective and Lipid-Lowering Effects.

Cardiac and hepatotoxicities are major concerns in the development of new drugs. Better alternatives to other treatments are being sought to protect these vital organs from the toxicities of these pharmaceuticals. In this regard, a preclinical study is designed to investigate the histopathological effects of a new succinimide derivative (Comp-1) on myocardial and liver tissues, and the biochemical effects on selected cardiac biomarkers, hepatic enzymes, and lipid profiles. For this, an initially lethal/toxic dose was determined, followed by a grouping of selected albino rats into five groups (each group had n = 6). The control group received daily oral saline for 8 days. The 5-FU (5-Fluorouracil) group received oral saline daily for 8 days, added with the administration of a single dose of 5-FU (150 mg/kg I.P.) on day 5 of the study. The atenolol group received oral atenolol (20 mg/kg) for 8 days and 5-FU (150 mg/kg I.P.) on day 5 of the protocol. Similarly, two groups of rats treated with test compound (Comp-1) were administered with 5 mg/kg I.P. and 10 mg/kg I.P. for 8 days, followed by 5-FU (150 mg/kg I.P.) on day 5. Toxicity induced by 5-FU was manifested by increases in the serum creatinine kinase myocardial band (CK-MB), troponin I (cTnI) and lactate dehydrogenase (LDH), lipid profile, and selected liver enzymes, including ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), BT (bilirubin total), and BD (direct bilirubin). These biomarkers were highly significantly decreased after the administration of the mentioned doses of the test compound (5 mg/kg and 10 mg/kg). Similarly, histological examination revealed cardiac and hepatic tissue toxicity by 5-FU. However, those toxic effects were also significantly recovered/improved after the administration of Comp-1 at the said doses. This derivative showed dose-dependent effects and was most effective at a dose of 10 mg/kg body weight. Binding energy data computed via docking simulations revealed that our compound interacts toward the human beta2-adrenergic G protein-coupled receptor (S = −7.89 kcal/mol) with a slight stronger affinity than the calcium channel T-type (S = −7.07 kcal/mol). In conclusion, the histological and biochemical results showed that the test compound (Comp-1) had prominent cardioprotective, hepatoprotective, and lipolytic effects against 5-FU-induced toxicity in the subjected animal model.

Succinimide Derivatives as Antioxidant Anticholinesterases, Anti-α-Amylase, and Anti-α-Glucosidase: In Vitro and In Silico Approaches.

Based on the diverse pharmacological potency and the structural features of succinimide, this research considered to synthesize succinimide derivatives. Moreover, these compounds were estimated for their biological potential in terms of anti-diabetic, anti-cholinesterase, and anti-oxidant capacities. The compounds were synthesized through Michael addition of various ketones to N-aryl maleimides. Similarly, the MOE software was used for the molecular docking study to explore the binding mode of the potent compounds against different enzymes. In the anti-cholinesterase activity, the compounds MSJ2 and MSJ10 exhibited outstanding activity against acetylcholinesterase (AChE), i.e., 91.90, 93.20%, and against butyrylcholinesterase (BChE), i.e., 97.30, 91.36% inhibitory potentials, respectively. The compounds MSJ9 and MSJ10 exhibited prominent α-glucosidase inhibitory potentials, i.e., 87.63 and 89.37 with IC50 value of 32 and 28.04 μM, respectively. Moreover, the compounds MSJ2 and MSJ10 revealed significant scavenging activity against DPPH free radicals with IC50 values of 2.59 and 2.52, while against ABTS displayed excellent scavenging potential with IC50 values 7.32 and 3.29 μM, respectively. The tentative results are added with molecular docking studies in the active sites of enzymes to predict the theoretical protein-ligand binding modes. Further detailed mechanism-based studies in animal models are essential for the in vivo evaluation of the potent compound.