Cyclic Imides Research Articles

Biocatalytic Reduction of Activated Cinnamic Acid Derivatives

The asymmetric reduction of C=C double bonds is a sought-after chemical transformation to obtain chiral molecules used in the synthesis of fine chemicals. Biocatalytic C=C double bond reduction is a particularly interesting transformation complementary to more established chemocatalytic methods. The enzymes capable of catalysing this reaction are called ene-reductases (ENEs). For the reaction to take place, ENEs need an electron withdrawing group (EWG) in conjugation with the double bond. Especially favourable EWGs are carbonyls and nitro groups; other EWGs, such as carboxylic acids, esters or nitriles, often give poor results. In this work, a substrate engineering strategy is proposed whereby a simple transformation of the carboxylic acid into a fluorinated ester or a cyclic imide allows to increase the ability of ENEs to reduce the conjugated double bond. Up to complete conversion of the substrates tested was observed with enzymes ENE-105 and *ENE-69.

Sustainable antimicrobial modified chitosan and its nanoparticles hydrogels: Synthesis and characterization

The target of the present study is the development of sustainable chitosan and chitosan nanoparticles-based heterocyclic compound hydrogels with antimicrobial properties. Sustainable antimicrobial new modified chitosan hydrogel (CS-3) was synthesized by the reaction of chitosan (CS) with 2-([4-[(1, 3-dioxoisoindolin-2-ylimino) methyl] phenyl] methyleneamino) isoindoline-1, 3-dione (3) via ring opening of cyclic imide moiety in compound (3). However, the modified chitosan nanoparticles hydrogel (CS-3 NPs) were prepared in-situ by an ionotropic gelation technique using sodium tripolyphosphate (TPP) as the cross-linking agent. The prepared hydrogels were characterized by FTIR, SEM, TEM, TGA, DSC and elemental analysis. The hydrogels were tested versus eight pathogenic strains of Gram +ve and Gram −ve bacteria and two fungi. The results revealed that hydrogels (CS-3) and (CS-3 NPs) showed higher antimicrobial activities than virgin (CS) and (CS-NPs). However, hydrogel (CS-3 NPs) showed the highest Minimal Inhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC) especially with Gram +ve bacteria (S. pyogenes) at 19.5 and 39 μg/ml compared to the standard antibiotic Ciprofloxacin at 19 and 38 μg/ml respectively.

Rapid and Controlled Organocatalyzed Ring-Opening Polymerization of 3S-(Isobutyl)morpholine-2,5-dione and Copolymerization with Lactide

Morpholine-2,5-diones are increasingly attractive monomers derived from amino-acids whose copolymerization with other monomers produces interesting biodegradable materials. In this study, the rapid and controlled organocatalyzed ring-opening polymerization of 3S-(isobutyl)morpholine-2,5-dione (MD) and its copolymerization with lactide (LA) was accomplished using 1,8-diazabicyclo(5,4,0)undec-7-ene and a thiourea (TU) cocatalyst. The amount of TU used for the polymerization was found to be fundamental for achieving good control. A range of polymers with molecular weights between 8.1 and 25.2 kg mol–1 was thus produced with narrow chain distributions (Đ = 1.13–1.18) in short periods (5 to 10 min). Secondly, copolymers with varying compositions (MD:LA = 25:75;50:50; 75:25) were prepared (11.2 to 12.7 kg mol–1; Đ = 1.09–1.26). The kinetics of these polymerizations suggest that concurrent thioimidate and cyclic imidate mechanisms are occurring and that these are governed by the quantity of TU in respect to MD.

The Solid-State Structures of Cyclic NH Carboximides

The patterns adopted in the solid state structures of over 300 cyclic NH carboximides as determined by X-ray diffraction are reviewed. While the analysis shows that the majority of these fit into just a few common patterns, a significant number exhibit more complex and interesting patterns involving the other functional groups present in addition to the cyclic imide.

Influence of the conformations of αA-crystallin peptides on the isomerization rates of aspartic acid residues

The isomerization rate of aspartic acid (Asp) residue is known to be affected by the three-dimensional structures of peptides and proteins. Although the isomerized Asp residues were experimentally observed, structural features which affect the isomerization cannot be elucidated sufficiently because of protein denaturation and aggregation. In this study, molecular dynamics (MD) simulations were conducted on three αA-crystallin peptides (T6, T10, and T18), each containing a single Asp residue with different isomerization rate (T18 > T6 > T10) to clarify the structural factors of Asp isomerization tendency. For MD trajectories, distances between side-chain carboxyl carbon of Asp and main-chain amide nitrogen of (n + 1) residue (Cγ–N distances), root mean square fluctuations (RMSFs), and polar surface areas for main-chain amide nitrogen of (n + 1) residues (PSAN) were calculated, because these structural features are considered to relate to the formations of cyclic imide intermediates. RMSFs and PSAN are indexes of peptide backbone flexibilities and solvent exposure of the amide nitrogen, respectively. The average Cγ–N distances of T10 was longer than those of the other two peptides. In addition, the peptide containing Asp residue with a higher isomerization rate showed higher flexibility of the peptide backbone around the Asp residue. PSAN for amide nitrogen in T18 were much larger than those of other two peptides. The computational results suggest that Asp-residue isomerization rates are affected by these factors.

Synthesis, characterization and in vitro antimicrobial activity of cyclic imide: Isoindoline-1, 3-dione derivatives

Synthesis, characterization and in vitro antimicrobial activity of cyclic imide: Isoindoline-1, 3-dione derivatives

Synthesis of New Cyclic Imides Derived from Safrole, Structure- and Ligand-based Approaches to Evaluate Potential New Multitarget Agents Against Species of Leishmania.

Leishmaniasis is a neglected disease that does not have adequate treatment. It affects around 12 million people around the world and is classified as a neglected disease by the World Health Organization. In this context, strategies to obtain new, more active and less toxic drugs should be stimulated. Sources of natural products combined with synthetic and chemoinformatic methodologies are strategies used to obtain molecules that are most likely to be effective against a specific disease. Computer-Aided Drug Design has become an indispensable tool in the pharmaceutical industry and academia in recent years and has been employed during various stages of the drug design process. Perform structure- and ligand-based approaches, synthesize and characterize some compounds with materials available in our laboratories to verify the method's efficiency. We created a database with 33 cyclic imides and evaluated their potential anti- Leishmanial activity (L. amazonensis and L. donovani) through ligand- and structure-based virtual screening. A diverse set selected from ChEMBL databanks of 818 structures (L. donovani) and 722 structures (L. amazonensis), with tested anti-Leishmanial activity against promastigotes forms, were classified according to pIC50 values to generate and validate a Random Forest model that shows higher statistical indices values. The structures of four different L. donovani enzymes were downloaded from the Protein Data Bank and the imides' structures were submitted to molecular docking. So, with available materials and technical feasibility of our laboratories, we have synthesized and characterized seven compounds through cyclization reactions between isosafrole and maleic anhydride followed by treatment with different amines to obtain new cyclic imides to evaluate their anti-Leishmanial activity. In silico study allowed us to suggest that the cyclic imides 516, 25, 31, 24, 32, 2, 3, 22 can be tested as potential multitarget molecules for leishmanial treatment, presenting activity probability against four strategic enzymes (Topoisomerase I, N-myristoyltransferase, cyclophilin and Oacetylserine sulfhydrylase). The compounds synthesized and tested presented pIC50 values less than 4.7 for Leishmania amazonensis. After combined approach evaluation, we have synthesized and characterized seven cyclic imides by IR, 1H NMR, 13C-APT NMR, COSY, HETCOR and HMBC. The compounds tested against promastigote forms of L. amazonensis presented pIC50 values less than 4.7, showing that our method was efficient in predicting true negative molecules.

Synthesis, anti-inflammatory, cytotoxic, and COX-1/2 inhibitory activities of cyclic imides bearing 3-benzenesulfonamide, oxime, and β-phenylalanine scaffolds: a molecular docking study

Cyclic imides containing 3-benzenesulfonamide, oxime, and β-phenylalanine derivatives were synthesised and evaluated to elucidate their in vivo anti-inflammatory and ulcerogenic activity and in vitro cytotoxic effects. Most active anti-inflammatory agents were subjected to in vitro COX-1/2 inhibition assay. 3-Benzenesulfonamides (2–4, and 9), oximes (11–13), and β-phenylalanine derivative (18) showed potential anti-inflammatory activities with 71.2–82.9% oedema inhibition relative to celecoxib and diclofenac (85.6 and 83.4%, respectively). Most active cyclic imides 4, 9, 12, 13, and 18 possessed ED50 of 35.4–45.3 mg kg−1 relative to that of celecoxib (34.1 mg kg−1). For the cytotoxic evaluation, the selected derivatives 2–6 and 8 exhibited weak positive cytotoxic effects (PCE = 2/59–5/59) at 10 μM compared to the standard drug, imatinib (PCE = 20/59). Cyclic imides bearing 3-benzenesulfonamide (2–5, and 9), acetophenone oxime (11–14, 18, and 19) exhibited high selectivity against COX-2 with SI > 55.6–333.3 relative to that for celecoxib [SI > 387.6]. β-Phenylalanine derivatives 21–24 and 28 were non-selective towards COX-1/2 isozymes as indicated by their SI of 0.46–0.68.

Manganese catalyzed selective hydrogenation of cyclic imides to diols and amines

Herein we report the selective hydrogenation of cyclic imides to diols and amines, homogeneously catalyzed for the first time by a complex of an earth-abundant metal, a manganese pincer complex.

Preparation of cyclic imides from alkene-tethered amides: application of homogeneous Cu(ii) catalytic systems.

A Cu-based homogeneous catalytic system was proposed for the preparation of imides from alkene-tethered amides. Here, O2 acted as a terminal oxidant and a cheap and easily available oxygen source. The cleavage of C Created by potrace 1.16, written by Peter Selinger 2001-2019 ]]> C bonds and the formation of C–N bonds were catalyzed by Cu(ii) salts with proper nitrogen-containing ligands under 100 °C. The synthesis approach has potential applications in pharmaceutical syntheses. Moreover, scaled-up experiments confirmed the practical applicability.

Activating Imides with Triflic Acid: A General Intramolecular Aldol Condensation Strategy Toward Indolizidine, Quinolizidine, and Valmerin Alkaloids.

A simple, inexpensive, step economic, and highly modular synthetic strategy to access izidine alkaloids is described. The key step is a TfOH-promoted intramolecular aldol condensation between enol and cyclic imide moieties. This cyclization strategy can be employed within an aza-Robinson annulation framework and represents a general tool to build fused bicyclic amines. To illustrate the power of this method, we describe the preparation of (±)-coniceine, (±)-quinolizidine, (±)-tashiromine, (±)-epilupinine, and the core of (±)-valmerins.

An efficient green synthesis of new benzothiazoles containing sulfonamide or cyclic imide moieties

AbstractAn efficient and convenient protocol for the one‐pot synthesis of new benzothiazoles bearing sulfonamide or cyclic imide moieties using Cesium salt of Wells‐Dawson heteropolyacid (Cs5HP2W18O62) as solid catalyst and water as solvent under ultrasound irradiation was reported. The reaction speed was remarkably catalyzed with the aid of ultrasound irradiation. Moreover, this approach prepares multiple other benefits such as operational ease, higher yields, and energy performance.

Visible-Light-Mediated Dearomatisation of Indoles and Pyrroles to Pharmaceuticals and Pesticides.

Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin derivatives are highly important for the synthesis of pharmaceuticals and bioactive compounds. Notably, this chemistry works excellently with N‐protected and protection‐free indoles. Additionally, this methodology can also be applied to dearomatise pyrrole derivatives to generate cyclic imides in a single step. Later this methodology was applied for the synthesis of four pharmaceuticals and a pesticide called dianthalexin B. Detailed mechanistic studies revealed the actual role of oxygen and photocatalyst.

C-H Bond Alkylation of Cyclic Amides with Maleimides via a Site-Selective-Determining Six-Membered Ruthenacycle.

The first example of a ruthenium-catalyzed C-H bond alkylation via six-membered ruthenacycles is presented. This is disclosed for the C-H bond alkylation of biologically relevant cyclic amides with maleimide derivatives. The cyclic tertiary amide core acted as a directing group (DG) enabling formation of six-membered cycloruthenated species responsible for the control of the regio- and site selectivity of the reaction as well as the excellent functional group tolerance. Unexpectedly, cyclic amides were found to be better DGs than pyridine-containing ones or cyclic imides for this type of C-H bond functionalization.

Structure-Based and Molecular Modeling Studies for the Discovery of Cyclic Imides as Reversible Cruzain Inhibitors With Potent Anti-Trypanosoma cruzi Activity.

Chagas disease causes ~10,000 deaths each year, mainly in Latin America, where it is endemic. The currently available chemotherapeutic agents are ineffective in the chronic stage of the disease, and the lack of pharmaceutical innovation for Chagas disease highlights the urgent need for the development of new drugs. The enzyme cruzain, the main cysteine protease of Trypanosoma cruzi, has been explored as a validated molecular target for drug discovery. Herein, the design, molecular modeling studies, synthesis, and biological evaluation of cyclic imides as cruzain inhibitors are described. Starting with a micromolar-range cruzain inhibitor (3a, IC50 = 2.2 μM), this molecular optimization strategy resulted in the nanomolar-range inhibitor 10j (IC50 = 0.6 μM), which is highly active against T. cruzi intracellular amastigotes (IC50 = 1.0 μM). Moreover, most compounds were selective toward T. cruzi over human fibroblasts, which were used as host cells, and are less toxic to hepatic cells than the marketed drug benznidazole. This study enabled the discovery of novel chemical diversity and established robust structure-activity relationships to guide the design of optimized cruzain inhibitors as new trypanocidal agents.

Chirality‐Embedded Nanographenes

AbstractThe development of chiral nanographenes has mostly been carried out by bottom‐up methods and examples of species developed by the post‐modification of nanographenes prepared by top‐down methods remain limited. We show that the attachment of chiral functional groups onto the edge of nanographenes generates chirality on the surface. X‐ray diffraction analysis and DFT calculations indicate that the chirality of the functional groups is transferred to the surface via steric interactions from the chiral center through the five‐membered cyclic imide to the nanographene edge. The exciton coupling between the p‐bromophenyl groups confirms that the functional groups are arranged on the armchair edges at distances that permit exciton coupling, which provides information about their relative orientation. These pieces of information help to elucidate the edge structure of nanographenes prepared by top‐down methods.

Chirality-Embedded Nanographenes.

The development of chiral nanographenes has mostly been carried out by bottom-up methods and examples of species developed by the post-modification of nanographenes prepared by top-down methods remain limited. We show that the attachment of chiral functional groups onto the edge of nanographenes generates chirality on the surface. X-ray diffraction analysis and DFT calculations indicate that the chirality of the functional groups is transferred to the surface via steric interactions from the chiral center through the five-membered cyclic imide to the nanographene edge. The exciton coupling between the p-bromophenyl groups confirms that the functional groups are arranged on the armchair edges at distances that permit exciton coupling, which provides information about their relative orientation. These pieces of information help to elucidate the edge structure of nanographenes prepared by top-down methods.

Synthesis of N-unsubstituted cyclic imides from anhydride with urea in deep eutectic solvent (DES) choline chloride/urea

N-Unsubstituted cyclic imides were readily synthesized in deep eutectic solvent (DES) choline chloride (ChCl)/urea from anhydrides with urea. Urea serves as both a DES component and a nitrogen source, which endows the protocol with advantages of smooth reaction, easy separation of products, simple recovery and recycling of ChCl/urea.

Iron-Binding and Anti-Fenton Properties of Novel Amino Acid-Derived Cyclic Imide Dioximes.

We present a novel route for the preparation of amino acid-derived cyclic imide dioxime derivatives. Readily accessible amino acids were conveniently converted to their corresponding cyclic imide dioximes in simple synthetic steps. The aim of this work was to describe and compare the iron-chelating and antioxidant properties of synthesized compounds in relation to their molecular structure, and in particular, which of those features are essential for iron(II)-chelating ability. The glutarimide dioxime moiety has been established as an iron(II)-binding motif and imparts potent anti-Fenton properties to the compounds. Compound 3 was shown to strongly suppress hydroxyl radical formation by preventing iron cycling via Fe-complexation. These findings provide insights into the structural requirements for achieving anti-Fenton activity and highlight the potential use of glutarimide dioximes as antioxidants.

Enantioselective Copper-Catalyzed Borylative Cyclization with Cyclic Imides.

An enantioselective borylative cyclization cascade utilizing cyclic imides has been developed. We employ a highly enantioselective borylcupration process that includes a 1,2-addition to a cyclic imide. The products contain a valuable hemiaminal and boronate handle for further elaborations within a congested framework. This work demonstrates the utility of cyclic imides as simple precursors to unlock access to sought-after polycyclic indolines. Futhermore, this report highlights the capability to harness reactive catalytic intermediates to exploit otherwise unreactive functional groups.