Succinimide Derivatives Research Articles

In silico-in vitro estimation of lipophilicity and permeability association for succinimide derivatives using chromatographic anisotropic systems and parallel artificial membrane permeability assay.

Passive permeability is one of the key features that determine absorbability and one of the most studied properties in the early phases of drug development. Newly synthesized succinimide derivatives from two different series (1-aryl-3-methylsuccinimides and 1-aryl-3-ethyl-3-methylsuccinimides) with high biological potential have been subjected to estimation of their passive permeability and their association with (a) experimentally obtained anisotropic lipophilicity, (b) in silico-calculated lipophilicity and (c) in silico-predicted permeability and absorbability. Non-cellular-based parallel artificial membrane permeability assay was applied for quantifying their passive permeation, expressed as logPapp . Passive permeation was governed by the lipophilicity of the analysed compounds, and anisotropic lipophilicity was related with statistically significant passive transcellular diffusion (r2 = 0.614, P < 0.001). Moreover, experimentally determined passive permeability, logPapp , was statistically significantly associated with both in silico-predicted absorption constant, ka (r2 = 0.7886, P < 0.001), and human intestinal absorption (HIA) in percentage (r2 = 0.484, P < 0.001), respectively. However, there was no statistically significant relationship between experimentally obtained permeability on non-cellular-based model and in silico-predicted Caco-2 permeability based on the predictions conducted on two different software. Based on the obtained results, anisotropic systems are promising surrogates for determining lipophilicity, except for compounds with acidic functional groups that are completely ionized under (pH = 7.4).

Comparative in-vitro anti-inflammatory, anticholinesterase and antidiabetic evaluation: computational and kinetic assessment of succinimides cyano-acetate derivatives

This research was planned to synthesize cyano-acetate derivatives of succinimide and evaluate its comparative biological efficacy as anti-inflammatory, anti-cholinesterase and anti-diabetic, which was further validated by molecular docking studies. The three cyano-acetate derivatives of succinimide including compound 23 Methyl 2-cyano-2-(2,5-dioxopyrrolidin-3-yl)acetate, compound 31 Methyl 2-cyano-2-(1-methyl-2,5-dioxopyrrolidin-3-yl)acetate and compound 44 Methyl 2-cyano-2-(1-ethyl-2,5-dioxopyrrolidin-3-yl) acetate were synthesized. The mentioned compounds were checked for in vitro anti-inflammatory, anti-cholinesterase and anti-diabetic (α-amylase inhibition) activity. To validate the in vitro results, computational studies were carried out using molecular operating environment to analyse the BE, i.e. binding energies of all synthesized compounds against the respective enzymes. The Compounds 23, 31, 44 exhibited anti-inflammatory via inhibiting COX-2 (IC50 value of 204.08, 68.60 and 50.93 µM, respectively), COX-1 (IC50 value of 287, 185, and 143 µM, respectively) and 5-LOX (IC50 value of 138, 50.76 and 20, 87 µM respectively). They exhibited choline-mimetic potential, such as compound 23, 31 and 44 inhibited AChE enzyme (IC50 value of 240, 174, and 134 µM, respectively) and BChE enzyme (IC50 value of 203, 134 and 97 µM, respectively). The Compounds 23, 31, 44 exhibited anti-diabetic effect via inhibiting α-amylase enzyme (IC50 values of 250, 106 and 60 µM, respectively). Molecular docking studies revealed that the synthesized compounds have good binding affinity in the binding pockets of AChE, BChE, COX-2, 5-LOX and α-amylase enzyme and showed high binding energies. The synthesized succinimide derivatives, i.e. compound 23, 31, 44 showed marked inhibitory activities against cyclooxygenase, lipoxygenase, α-amylase and cholinesterase enzymes. Among these three, compound 44 and 31 showed strong anti-inflammatory and anti-diabetic activity while they displayed moderate anti-cholinesterase activity supported by molecular docking results. Communicated by Ramaswamy H. Sarma

Synthesis, Antioxidant, and Antidiabetic Activities of Ketone Derivatives of Succinimide.

The prevalence of diabetes mellitus is persistently increasing globally creating a serious public health affliction. Diabetes mellitus is categorized into two major types designated as type I and Type II. Type I diabetes mellitus is characterized by complete lack of secretion of insulin, while Type II diabetes mellitus is the resistance of peripheral tissues to the action of insulin and inadequate compensatory secretion of insulin. Chronic hyperglycemia associated with diabetes causes failure of cardiovascular system, nervous system, kidneys, and eyes. At present, different types of drugs are used for the management of diabetes, but each of them is associated with more or less serious side effects. Therefore, we need to develop new therapeutic agents that have better efficacy and safety profile. In this study, three ketone derivatives of succinimides were synthesized based on Michael addition and characterized using NMR. All the synthesized compounds were checked for their in vitro α-amylase and α-glucosidase inhibitory activities. Further the synthesized compounds were also explored for their antioxidant activities, i.e, DPPH and ABTS assays. Based on the in vitro results, the synthesized compounds were further evaluated for in vivo antidiabetic activity. The synthesized compounds were (2-oxocyclohexyl)-1-phenylpyrrolidine-2,5-dione (BW1), benzyl-3-(2-oxocyclohexyl) pyrrolidine-2,5-dione (BW2), and (4-bromophenyl)-3-(2-oxocyclohexyl) pyrrolidine-2,5-dione (BW3). BW1 showed the highest inhibitory activity for DPPH causing 83.03 ± 0.48 at 500 μg/ml with IC50 value of 10.84 μg/ml and highest inhibitory activity for ABTS causing 78.35 ± 0.23 at 500 μg/ml with IC50 value of 9.40 μg/ml against ascorbic acid used as standard. BW1 also exhibited the highest activity against α-amylase and α-glucosidase inhibition causing 81.60 ± 0.00 at concentrations of 500 μg/ml with IC50 value of 13.90 μg/ml and 89.08 ± 1.04 at concentrations of 500 μg/ml with IC50 value of 10.49 μg/ml, respectively, against the standard drug acarbose.

Synthesis, characterization and performance of succinimide derivatives as anti-corrosion and anti-scalant in petroleum applications

This paper is aimed to prepare two succinimide derivatives namely ; [N1, N4-bis((2-hydroxyethyl) carbamothioyl) succinimide (I) and N1,N4-bis(bis(2-hydroxyethyl)carbamothioyl) succinimide (II)] and confirmation their chemical structure by FTIR, Mass and 1H NMR spectroscopic techniques. The performance of the prepared compounds as anti-corrosion was tested using electrochemical techniques, while the anti-scalant performance evaluated using NACE standard testing method (T1A0374-90). The potentiodynamic polarization method (PDP) showed that the two succinimide derivatives acted as mixed type inhibitors. The investigated succinimide derivatives obeyed Langmuir adsorption isotherm. The maximum efficiency of compound (II) reached 93.1% as anticorrosion and 91.5% as anti-scalant. The results exhibited that the scale inhibition efficiency enhanced via rising the doses of these succinimide derivatives. Finally, the experimental data were supported by theoretical calculations.

Highly efficient and fast synthesis of di-iodinated succinimide derivatives from 1,6-enyne and I2 under air at room temperature

A metal-free, additive-free, and practical method for the synthesis of diiodinated succinimide derivatives has been achieved under mild conditions.

Cover Feature: Photoredox‐Induced Deaminative Radical‐Cationic Three‐Component Couplings with N‐Alkylpyridinium Salts and Alkenes (ChemPhotoChem 11/2021)

The Cover Feature shows a radical three-component coupling driven by visible light photoredox catalysis. Single electron transfer (SET) reduction of N-alkylpyridinium salts liberates nucleophilic carbon radicals that successively couple with an acceptor and a donor alkene, enabling a stereoselective synthesis of new succinimide derivatives. Cover image made by Marcin Henk Kowalski. More information can be found in the Communication by Malte Brasholz and co-workers.

Iron-catalyzed hydroaminocarbonylation of alkynes to produce succinimides with NH4HCO3

Succinimide derivatives are valuable compounds in synthesis of natural products and pharmaceuticals. A catalytic hydroaminocarbonylation reaction was developed for the synthesis of succinimides from alkynes, CO and NH4HCO3. The novel transformation proceeds in the presence of Fe3(CO)12 without the need for expensive ligands or additives. Various substituted alkynes are selectively transformed into corresponding succinimides in good yields. Preliminary mechanistic studies suggest that NH4HCO3 plays an important role in the formation and stabilization of iron catalyst.

Synthesis, characterization, anticancer activity, and molecular docking of novel maleimide–succinimide derivatives

Synthesis, characterization, anticancer activity, and molecular docking of novel maleimide–succinimide derivatives

Synthesis of Succinimides via Intramolecular Alder-Ene Reaction of 1,6-Enynes.

A novel and convenient method has been developed for the facile synthesis of functionalized succinimide derivatives via intramolecular Alder-ene reaction of 1,6-enynes. This reaction features mild and metal-free reaction conditions, which offers a green and efficient entry to synthetically important succinimide scaffolds. Preliminary mechanistic studies suggest that a diradical intermediate might be involved in this transformation.

Clusteroluminescence from Cluster Excitons in Small Heterocyclics Free of Aromatic Rings.

The study of nonconventional luminescence is important for revealing the luminescence of natural systems and has gradually drawn the attention of researchers in recent years. However, the underlying mechanism is still inexplicable. Herein, the luminescence behavior of two series of simple, heteroatom‐containing small molecules without aromatic rings, i.e., maleimide and succinimide derivatives, are studied to gain further mechanistic insight into the nonconventional luminescence process. It has been unveiled that all the molecules exhibit bright and visible luminescence in concentrated solution and solid state and the formation of clusters is the root cause for such behaviors, which can effectively increase the possibility of both the nonradiative n–π* and favorable π–π* transitions and stabilize the excitons formed in the excited state. The distinctive luminescent phenomena and intriguing mechanism presented in this work will be significant for understanding the mechanism of clusteroluminescence and provide new strategies for the rational design of novel luminescent materials.

Computational Screening of Lewis Acid Catalysts for the Ene Reaction between Maleic Anhydride and Polyisobutylene

Polyisobutenyl succinic anhydrides (PIBSAs) and their succinimide derivatives are one of the most important additives in lubricant and fuel formulations. These additives are commonly synthesized th...

Synthesis and Antimicrobial studies of some Mannich Bases of Succinimide derivatives

Synthesis and Antimicrobial studies of some Mannich Bases of Succinimide derivatives

On-Demand Detachment of Succinimides on Cysteine to Facilitate (Semi)Synthesis of Challenging Proteins.

The maleimide group is a widely used reagent for bioconjugation of peptides, proteins, and oligonucleotides employing Michael addition and Diels–Alder cycloaddition reactions. However, the utility of this functionality in chemical synthesis of peptides and proteins remains unexplored. We report, for the first time that PdII complexes can mediate the efficient removal of various succinimide derivatives in aqueous conditions. Succinimide removal by PdII was applied for the synthesis of two ubiquitin activity-based probes (Ub-ABPs) employing solid phase chemical ligation (SPCL). SPCL was achieved through a sequential three segment ligation on a polymer support via a maleimide anchor. The obtained probes successfully formed the expected covalent complexes with deubiquitinating enzymes (DUBs) USP2 and USP7, highlighting the use of our new method for efficient preparation of unique synthetic proteins. Importantly, we demonstrate the advantages of our newly developed method for the protection and deprotection of native cysteine with a succinimide group in a peptide fragment derived from thioredoxin-1 (Trx-1) obtained via intein based expression to enable ligation/desulfurization and subsequent disulfide bond formation in a one-pot process.

NGR-TNF Engineering with an N-Terminal Serine Reduces Degradation and Post-Translational Modifications and Improves Its Tumor-Targeting Activity.

The therapeutic index of cytokines in cancer therapy can be increased by targeting strategies based on protein engineering with peptides containing the CNGRC (NGR) motif, a ligand that recognizes CD13-positive tumor vessels. We show here that the targeting domain of recombinant CNGRC-cytokine fusion proteins, such as NGR-TNF (a CNGRC-tumor necrosis factor-α (TNF) conjugate used in clinical studies) and NGR-EMAP-II, undergoes various post-translational modification and degradation reactions that lead to the formation of markedly heterogeneous products. These modifications include N-terminal cysteine acetylation or the formation of various asparagine degradation products, the latter owing to intramolecular interactions of the cysteine α-amino group with asparagine and/or its succinimide derivative. Blocking the cysteine α-amino group with a serine (SCNGRC) reduced both post-translational and degradation reactions. Furthermore, the serine residue reduced the asparagine deamidation rate to isoaspartate (another degradation product) and improved the affinity of NGR for CD13. Accordingly, genetic engineering of NGR-TNF with the N-terminal serine produced a more stable and homogeneous drug (called S-NGR-TNF) with improved antitumor activity in tumor-bearing mice, either when used alone or in combination with chemotherapy. In conclusion, the targeting domain of NGR-cytokine conjugates can undergo various untoward modification and degradation reactions, which can be markedly reduced by fusing a serine to the N-terminus. The SCNGRC peptide may represent a ligand for cytokine delivery to tumors more robust than conventional CNGRC. The S-NGR-TNF conjugate (more stable, homogeneous, and active than NGR-TNF) could be rapidly developed for clinical trials.

Comparative chemometric and quantitative structure-retention relationship analysis of anisotropic lipophilicity of 1-arylsuccinimide derivatives determined in high-performance thin-layer chromatography system with aprotic solvents

Numerous structurally different amides and imides including succinimide derivatives exhibit diverse bioactive potential. The development of new compounds requires rationalization in the design in order to provide structural changes that guarantee favorable physico-chemical properties, pharmacological activity and safety. In the present research, a comprehensive study with comparison of the chromatographic lipophilicity and other physico-chemical properties of five groups of 1-arylsuccinimide derivatives was conducted. The chemometric analysis of their physico-chemical properties was carried out by using unsupervised (hierarchical cluster analysis and principal component analysis) and supervised pattern recognition methods (linear discriminant analysis), while the correlations between the in silico molecular features and chromatographic lipophilicity were examined applying linear and non-linear Quantitative Structure-Retention Relationship (QSRR) approaches. The main aim of the conducted research was to determine similarities and dissimilarities among the studied 1-arylsuccinimides, to point out the molecular features which have significant influence on their lipophilicity, as well as to establish high-quality QSRR models which can be used in prediction of chromatographic lipophilicity of structurally similar 1-arylsuccinimides. This study is a continuation of analysis and determination of the physico-chemical properties of 1-arylsuccinimides which could be important guidelines in further in vitro and eventually in vivo studies of their biological potential.

Time-Economical Radical Cascade Cyclization/Haloazidation of 1,6-Enynes: Construction of Highly Functional Succinimide Derivatives.

A "time-economical" radical cascade cyclization/haloazidation of 1,6-enynes provides a direct approach to access highly functional succinimide compounds. Moderate to excellent yields along with excellent Z/E ratio were obtained under the reaction features of broad substrate scope, good functional group tolerance, and mild reaction conditions.

Cobalt(III)-Catalyzed Redox-Neutral Coupling of Acrylamides with Activated Alkenes via C–H Bond Activation

A cobalt(III)-catalyzed coupling of substituted acrylamides with maleimides in the presence of 30 mol% pivalic acid providing olefin-migrated succinimide derivatives in a redox-neutral manner is described. The coupling reaction was examined with various substituted acrylamides and maleimides. The scope of the C–H alkylation reaction was also examined with substituted acrylates. A possible reaction mechanism involving a five-membered cobaltocycle as a key intermediate is proposed.

Pharmacological Evaluation of Aldehydic-Pyrrolidinedione Against HCT-116, MDA-MB231, NIH/3T3, MCF-7 Cancer Cell Lines, Antioxidant and Enzyme Inhibition Studies.

PurposeThe current work was designed to synthesize a bioactive derivative of succinimide and evaluate it for anti-Alzheimer, anticancer and anti-diabetic potentials.MethodsThe compound was synthesized by Michael addition of butyraldehyde with N-phenylmaleimide. The synthesized compound was screened for biological potentials including anti-cholinesterase, in-vitro anti-diabetic, antioxidant and anthelmintic potentials. The anti-cholinesterase potential was evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), anti-diabetic potential against α-glucosidase, antioxidant potential against ABTS, DPPH and H2O2 and anthelmintic potential against Perethima posthuma and Ascaridia galli respectively.ResultsThe compound demonstrated significant AChE and BChE inhibition i.e., 71.34±1.92 and 73.42 ±1.92 at the concentration of 1000 µg/mL respectively. Other dilutions exhibited concentration-dependent inhibitory activity against both enzymes. In the MTT assay, the newly synthesized compound was found active against all of the cell lines viz, HCT-116, MDA-MB231, NIH/3T3 and MCF-7 and the highest cytotoxicity potential was observed against the colon cancer cell line (HCT-116) with an IC50 value of 78 µg/mL exhibiting its highest potential. Moreover, the compound exhibited prominent α-glucosidase inhibitory potentials (79.86±2.54% at 1000 µg/mL) with IC50 value of 156.23 µg/mL. Further, our test compound exhibited considerable scavenging activity against DPPH, ABTS and H2O2 free radicals with percent inhibitions of 75.84±1.58, 72.85±1.17 and 54.82±1.82 and IC50 values of 84.36, 139.74 and 752.21 µg/mL respectively. Our test sample exhibited significant anthelmintic potentials. It demonstrated significant paralysis and death of the test worms in an unbelievably short time in comparison with albendazole.ConclusionGoing into the detail of all observations, it may be deduced that the newly synthesized succinimide derivative could be an important drug candidate against neurodegenerative disorders like Alzheimer’s disease, cancer, diabetes mellitus and worms. Further detailed studies in animal models are required for in-vivo analysis of the compound.

Chromatographic and computational screening of anisotropic lipophilicity and pharmacokinetics of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimides

The present study is focused on a series of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimide derivatives, as potential anticonvulsants. The retention behavior of eleven succinimide derivatives was determined by using reversed phase high performance liquid chromatography (RP-HPLC) and reversed phase high performance thin layer chromatography (RP-HPTLC). The estimated retention behavior was correlated with partition (logP) and distribution coefficients (logD). These high correlations pointed out that the determined retention parameters (logk0 and RM0) can be considered chromatographic (anisotropic) lipophilicity of the studied succinimide derivatives. The structural properties, which dominantly affect the chromatographic lipophilicity, were determined as well. The significant correlations between the chromatographic lipophilicity and plasma protein binding (PPB), Madin-Darby Canine Kidney (MDCK) cells permeability, volume of distribution (Vd) and absorption constant (Ka) indicate the strong influence of lipophilicity on pharmacokinetics of 1-aryl-3-ethyl-3-methylsuccinimide derivatives. These derivatives have also been tested applying Comprehensive Medicinal Chemistry (CMC) drug-like rules which confirmed their drug-like properties. Besides, their blood-brain penetration (BBB) ability has been estimated applying the set of Clark’s rules and by using Pre-ADMET software. Regarding toxicity, it was predicted that only one compound from the set might have toxic effects by blocking the hERG potassium channel. The present study reveals which molecular features in the structure of novel succinimide derivatives could be crucial for their lipophilicity, and consequently for their pharmacokinetic properties. The results indicate that the newly synthesized series of succinimide derivatives should be further considered in design of novel anticonvulsants.

Choline Chloride/ Urea as Mild Media for the Synthesis of the Chromonyl Amidodiester Fragments and Succinimide Derivatives

AbstractA simple, green protocol has been accomplished for the synthesis of amidoesters 5 a‐k in choline chloride/urea (1:2) through multicomponent reaction of 3‐formyl chromone, Meldrum's acid, isocyanides and primary alcohols via a domino reaction. Carrying out the reaction using trifluoroethanol led to succinimide derivatives 6 a‐d. Easy work‐up, selectivity, and good to excellent yields are the advantages of this protocol.