Carbonyldiimidazole Research Articles

Synthesis and evaluation of chromone derivatives as inhibitors of monoamine oxidase.

Based on reports that chromone compounds are good potency inhibitors of monoamine oxidase (MAO), the present study evaluates the effect of substitution with flexible side chains on the 3 position on MAO inhibition potency. Fifteen chromone derivatives were synthesised by reacting aromatic and aliphatic amines and alcohols with chromone 3-carboxylic acid in the presence of carbonyldiimidazole (CDI). This yielded chromane-2,4-dione and ester chromone derivatives. Generally, the esters exhibited weak MAO inhibition, while the chromane-2,4-dione derivatives showed promise as selective MAO-B inhibitors with IC50 values in the micromolar range. Compound 14b, 3-[(benzylamino)methylidene]-3,4-dihydro-2H-1-benzopyran-2,4-dione, was the most potent MAO-B inhibitor with an IC50 value of 638µM. This compound was shown to be a reversible and competitive MAO-B inhibitor with a Ki of 94µM. In conclusion, the effect of chain elongation and introduction of flexible substituents on position 3 of chromone were explored and the results showed that aminomethylidene substitution is preferable over ester substitution. Good potency MAO-B inhibitors may act as leads for the design and development of therapy for Parkinson's disease where these agents reduce the central metabolism of dopamine.

A route to access imidazol[1,5-a]indole-1,3-diones and pyrrolo[1,2-c]imidazole-1,3-diones.

A novel and practical route to synthesize imidazol[1,5-a]indoles and pyrrolo[1,2-c]imidazoles via N-H functionalization has been developed. Indole-2-carboxylic acid or pyrrole-2-carboxylic acid with diverse aniline groups and carbonyldiimidazole (CDI), in the presence of a base under microwave conditions, resulted in imidazol[1,5-a]indoles and pyrrolo[1,2-c]imidazoles, respectively. The present method is free of work-up and no need for column chromatography. Both title scaffolds can serve as useful heterocyclic scaffolds in medicinal chemistry as such, or they can be used as building blocks to construct different classes of useful compounds.

Metal-Organic Framework MIL-101-NH2-Supported Acetate-Based Butylimidazolium Ionic Liquid as a Highly Efficient Heterogeneous Catalyst for the Synthesis of 3-Aryl-2-oxazolidinones.

A novel heterogeneous catalyst, the ionic liquid (IL) of 1-butyl-3-methylimidazolium acetate (BmimOAc) immobilized on MIL-101-NH2, denoted as IL(OAc-)-MIL-101-NH2, was prepared by the "ship-in-a-bottle" strategy. The IL of BmimOAc was prepared in the MIL-101-NH2 nanocages primordially, in which the condensation product of MIL-101-NH2's amine group with 1,1'-carbonyldiimidazole (CDI) reacted with 1-bromo butane, and then the intermediate exchanged with potassium acetate. The structure and physicochemical properties of IL(OAc-)-MIL-101-NH2 were characterized by powder X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, DRS UV-vis, nitrogen adsorption-desorption, and elemental analysis. The results indicated that BmimOAc was anchored in the MIL-101-NH2 skeleton via the acylamino group and confined in the nanocages in the form of a single molecule. The composite material of IL(OAc-)-MIL-101-NH2 exhibited excellent catalytic activity and catalytically synthesized 3-aryl-2-oxazolone in an excellent yield of 92%. It can be reused up to six times without noteworthy loss of its activity and demonstrated distinct size-selective property for substrates. It was conjectured that the diffusion kinetics of reactants could be controlled by the aperture size of the metal-organic framework support.

A Convenient Protocol for the Synthesis of Fatty Acid Amides

Several classes of biologically occurring fatty acid amides have been reported from mammalian and plant sources. Many amides conjugated with fatty acids of mammalian origin exhibit specific activation of individual receptors. Their potential as pharmacological tools or as lead compounds towards the development of novel therapeutics is of great interest. Hence, access to such amides by a practical, high-yielding and scalable protocol without affecting the geometry or position of sensitive functionalities is needed. A protocol that meets all these requirements involves activation of the corresponding acid with carbonyl diimidazole (CDI) followed by reaction with the desired amine or its hydrochloride. More than fifty compounds have been prepared in generally high yields.

An indirect competitive enzyme-linked immunosorbent assay toward the standardization of Pueraria candollei based on its unique isoflavonoid, kwakhurin

Kwakhurin (Kwa) is a plant secondary metabolite solely present in Pueraria candollei var. mirifica (P. candollei), which has long been used as a Thai traditional herb for estrogen replacement therapy. Recently, health hazards have arisen in Japan regarding P. candollei-derived products containing potent estrogenic compounds. Therefore, the development of standardization methods for P. candollei materials is an urgent problem requiring resolution. The enzyme-linked immunosorbent assay (ELISA) is an effective analytical technique because it enables the development of sensitive and specific assays of the target compound through antigen−antibody reaction. Here, we produced a monoclonal antibody against Kwa (MAb 11F) by immunizing Kwa-bovine serum albumin (BSA) conjugates prepared using an N,N′-carbonyldiimidazole (CDI) mediated method. Stability and cross-reactivity tests of MAb 11F revealed that the MAb 11F is stable for at least 4 months at 4 °C and is highly specific to Kwa. The detectable concentration range of an indirect competitive ELISA (icELISA) using MAb 11F exhibited values of 1.53–48.8 ng/mL with the limit of detection (LOD) of 1.13 ng/mL. Validation analyses revealed that the developed icELISA is precise, accurate, and reliable enough to be applied to P. candollei-derived samples and products for their standardization.

Radiolabeled Molecular Imaging Probes for the In Vivo Evaluation of Cellulose Nanocrystals for Biomedical Applications.

Cellulose nanocrystals (CNCs) have remarkable potential to improve the delivery of diagnostic and therapeutic agents to tumors; however, the in vivo studies on CNC biodistribution are still limited. We developed CNC-based imaging probes for the in vitro and in vivo evaluation using two labeling strategies: site-specific hydrazone linkage to the terminal aldehyde of the CNC and nonsite-specific activation using 1,1'-carbonyldiimidazole (CDI). The in vivo behavior of unmodified CNC, DOTA-CNC (ald.), and DOTA-CNC (OH) was investigated in healthy and 4T1 breast cancer mouse models. They displayed good biocompatibility in cell models. Moreover, the biodistribution profile and SPECT/CT imaging confirmed that the accumulation of 111In-labeled DOTA-CNC (ald.) and 111In-DOTA-CNC (OH) was primarily in hepatic, splenic, and pulmonary ducts in accordance with the clearance of nontargeted nanoparticles. The developed CNC imaging probes can be used to obtain information with noninvasive imaging on the behavior in vivo to guide structural optimization for targeted delivery.

Synthesis of chemically crosslinked pullulan/gelatin-based extracellular matrix-mimetic gels

In order to develop pullulan/gelatin-based gels as potential extracellular matrix-mimetic scaffolds, a “one-step” synthesis method using 1,1′‑carbonyldiimidazole (CDI) as activator in DMSO under mild conditions was reported for the first time. Particularly, in contrast to conventional critical requirement of absolute dryness for CDI, it was interesting to find that the formation of gels could be accomplished in the presence of aqueous solvent within a much shorter time, while obtaining improved mechanical properties as demonstrated by compressive tests. UV–Visible spectroscopy, NMR spectrum, TEM and SEM analysis have been employed to evaluate the underlying reaction mechanisms. This method implied that absolute dryness might not be necessary for using CDI as activator in certain cases. This method also represents a new rapid and efficient approach for synthesizing a great variety of chemically crosslinked polysaccharide/protein-based gels as promising material platform potential for tissue engineering and drug delivery applications.

Practical Considerations for the Formation of Acyl Imidazolides from Carboxylic Acids and N,N′-Carbonyldiimidazole: The Role of Acid Catalysis

The conversion of carboxylic acids to acyl imidazolides using N,N′-carbonyldiimidazole (CDI) is hampered by the presence of alkali salts of the carboxylic acid, resulting in incomplete reactions, which cannot be driven to completion with excess CDI. Addition of an exogenous proton source reverses this effect. Sparging of the reaction mixture with carbon dioxide is also effective, presumably due to the formation of the carbamic acid of imidazole, which acts as a proton source. These results suggest that acyl imidazolide formation is subject to acid catalysis. The acceleration of acyl imidazolide formation using triflic acid or imidazolium triflate, as catalyst, is demonstrated.

Investigation of Cyclodextrin-Based Nanosponges for Solubility and Bioavailability Enhancement of Rilpivirine.

Rilpivrine is BCS class II drug used for treatment of HIV infection. The drug has low aqueous solubility (0.0166mg/ml) and dissolution rate leading to low bioavailability (32%). Aim of this work was to enhance solubility and dissolution of rilpivirine using beta-cyclodextrin-based nanosponges. These nanosponges are biocompatible nanoporous particles having high loading capacity to form supramolecular inclusion and non-inclusion complexes with hydrophilic and lipophilic drugs for solubility enhancement. Beta-cyclodextrin was crosslinked with carbonyl diimidazole and pyromellitic dianhydride to prepare nanosponges. The nanosponges were loaded with rilpivirine by solvent evaporation method. Binary and ternary complexes of drug with β-CD, HP-β-CD, nanosponges, and tocopherol polyethylene glycol succinate were prepared and characterized by phase solubility, saturation solubility in different media, in vitro dissolution, and in vivo pharmacokinetics. Spectral analysis by Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry was performed. Results obtained from spectral characterization confirmed inclusion complexation. Phase solubility studies indicated stable complex formation. Saturation solubility was found to be 10-13-folds higher with ternary complexes in distilled water and 12-14-fold higher in 0.1N HCl. Solubility enhancement was evident in biorelevant media. Molecular modeling studies revealed possible mode of entrapment of rilpivirine within β-CD cavities. A 3-fold increase in dissolution with ternary complexes was observed. Animal studies revealed nearly 2-fold increase in oral bioavailability of rilpivirine. It was inferred that electronic interactions, hydrogen bonding, and van der Waals forces are involved in the supramolecular interactions.

Immobilization of organophosphorus hydrolase enzyme by covalent attachment on modified cellulose microfibers using different chemical activation strategies: Characterization and stability studies

Abstract The plant cellulose powder was activated by two different methods using 1,4-butanediol diglycidyl ether (BTDE) and 1,1′-Carbonyldiimidazole (CDI) as the chemical coupling agents. Organophosphorus hydrolase (OPH) from Flavobacterium ATCC 27551 was immobilized on any of activated support through covalent bonding. The optimal conditions of affecting parameters on enzyme immobilization in both methods were found, and it was demonstrated that the highest activity yields of immobilized OPH onto epoxy and CDI treated cellulose were 68.32% and 73.51%, respectively. The surface treatment of cellulose via covalent coupling with BTDE and CDI agents was proved by FTIR analysis. The kinetic constants of the free and immobilized enzymes were determined, and it was showed that both immobilization techniques moderately increased the Km value of the free OPH. The improvements in storage and thermal stability were investigated and depicted that the half-life of immobilized OPH over the surface of epoxy modified cellulose had a better growth compared to the free and immobilized enzymes onto CDI treated support. Also, the pH stability of the immobilized preparations was enhanced relative to the free counterpart and revealed that all enzyme samples would have the same optimum pH value for stability at 9.0. Additionally, the immobilized OPH onto epoxy and CDI activated cellulose retained about 59% and 68% of their initial activity after ten turns of batch operation, respectively. The results demonstrated the high performance of OPH enzyme in immobilized state onto an inexpensive support with the potential of industrial applications.

Unsaturated Polyester Resin Nanocomposites Containing ZnO Modified with Oleic Acid Activated by N,N'-Carbonyldiimidazole.

Hydrophobic zinc oxide (ZnO) nanoparticles were produced through grafting aminopropyltriethoxysilane (APS) and oleic acid (OA), which was activated by N,N′-carbonyldiimidazole (CDI). The functional group containing ZnO nanoparticles were incorporated into unsaturated polyester (UP) resin, and their dispersibility in the UP matrix and effects on the properties of UP/ZnO nanocomposites were investigated. ZnO nanoparticles modified by APS and OA activated by CDI, (CDI–OA–APS–ZnO), can be homogeneously dispersed as supported by transmission electron microscopy (TEM) investigations and had been encapsulated in the UP resin. CDI–OA–APS–ZnO nanoparticles were embedded in the net structure of the UP composites through chemical bonds between oleic acid, styrene, and polyester resin, which significantly influence the cure reaction of UP resin and the properties of UP composites. Thermogravimetric analysis (TGA) results show that the incorporation of ZnO nanoparticles could improve the thermal stability of UP when thermal cracking temperature exceeds 365 °C. The exothermic peak and the initial temperature of cure reaction of the UP resin decreased with increasing ZnO content. The tensile strength and bending strength of UP/CDI–OA–APS–ZnO nanocomposites increased by 91.4% and 71.3% when 3 wt % CDI–OA–APS–ZnO nanoparticles was added into the composites, respectively, compared with pure UP resin.

The synthesis of 2-amino-4(3H)-quinazolinones and related heterocycles via a mild electrocyclization of aryl guanidines

A new method for the preparation of 2-amino-4(3H)-quinazolinones and similar fused heterocycles is described. Simply warming a mixture of an aryl guanidine and carbonyl diimidazole in acetonitrile results in formation of a putative N-amidinoisocyanate intermediate which undergoes a 6π-electron electrocyclic reaction with the aryl ring to generate the quinazolinone ring system. The mild conditions are compatible with a variety of functional groups, and the reaction is shown to be successful on multigram scale.

Structure, Performance and Crystallization Behavior of Poly (Lactic Acid)/Humic Acid Amide Composites

ABSTRACTHumic acid amide (HA-amide) was prepared by amidation of HA and dodecylamine (DDA) with carbonyl diimidazole (CDI) as coupling reagent. Furthermore, HA-amide was added to poly (lactic acid) (PLA) as a nucleating agent to prepare poly (lactic acid)/humic acid amide composites (PLA/HA-amide) by melt blending. The structure and performance of PLA/HA-amide composites were investigated by thermogravimetric analysis (TG), differential scanning calorimetry (DSC), polarized optical microscopy (POM), and rheological analysis. Non-isothermal crystallization kinetics showed the HA-amide enhanced the crystallization rate of PLA. The results of crystallization behavior of PLA/HA-amide composites showed that HA-amide was an efficient nucleating agent of PLA.

1,1'-Carbonyldiimidazole (CDI) Mediated Facile Synthesis, Structural Characterization, Antimicrobial Activity, and in-silico Studies of Coumarin- 3-carboxamide Derivatives.

Despite the availability of a variety of antibacterial agents, re-emergence of pathogenic bacteria is still a serious medical concern. So, identification of new, safer, and selective antibacterial agents is the key interest in the medicinal chemistry research. To explore the antimicrobial activity of coumarin-3-carboxamides for a range of bacterial and fungal strains, twenty eight derivatives were synthesized by the reaction of coumarin-3-carboxylic acid with a variety of aniline derivatives in the presence of 1,1'-carbonyldiimidazole (CDI). All compounds were structurally characterized by different spectroscopic techniques EI-MS, HREI-MS, 1H-NMR, 13C-NMR, and evaluated for antimicrobial activities (antibacterial and antifungal). A number of compounds showed good to weak antibacterial activity against various strains of Gram-positive and Gram-negative bacteria. Amongst them, compound 28 displayed noticeable inhibition against five strains of Gram-positive (Bacillus subtilis, Corynebacterium xerosis, Staphylococcus aureus, Streptococcus faecalis, and MRSA) and four strains of Gram-negative bacteria (Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter aerogene, and Shigella dysenteria). However, none of the compounds showed antifungal activity against tested fungi. MIC values were determined for most of the active compounds 2, 15, and 28 against particular bacterial cultures. In silico studies were performed on the most active compound 28 in order to specify and verify the target for antibacterial activity of synthetic coumarin-3-carboxamide derivatives. The cytotoxicity of these compounds on mammalian cells is unknown yet but we are planning to carry out research on the cytotoxic aspect of these compounds in future. The newly identified compounds may serve as lead molecules for the future research regarding the identification of new antibacterial agents.

Green Synthesis of 1,1'-Carbonyldiimidazole Using Copper Oxide Nanofiber as a Heterogeneous Catalyst.

Poly(vinyl pyrrolidone) (PVP)/copper oxide composite nanofibers were prepared by electrospinning technique using PVP and copper acetate as precursors and calcinated at high temperature to yield polymer free, phase pure copper oxide nanofibers (CuO NFs). The powder X-ray diffraction (XRD) pattern, transmission electron microscopic (TEM) images and selected area electron diffraction pattern (SAED) results showed that the calcinated CuO NFs were crystalline with 166 nm diameter and monoclinic in phase. From the catalytic application point of view, the newly prepared electrospun CuO NFs were tested for N-arylation of imidazole using aryl halides. To our surprise, 1,1'-carbonyldiimidazole (CDI) was obtained under the conditions of air and nitrogen atmosphere. Furthermore, the same product CDI was obtained from the reactions where in no aryl halide was involved but with imidazole alone as substrate. Our methodology to prepare CDI is free from the use of toxic phosgene as carbonyl source, as reported earlier. Hence, the present process possesses some advantages such as green and cost effective alternate for the existing synthesis method.

Synthesis of Novel 3D-Rich α-Amino Acid-Derived 3-Pyrazolidinones.

Synthetic approaches towards novel 3-pyrazolidinone derivatives functionalized at positions N(1) and/or C(5) were studied. 5-Aminoalkyl-3-pyrazolidinones were prepared in four steps from N-protected glycines via Masamune-Claisen homologation, reduction, O-mesylation, and cyclisation with a hydrazine derivative. The free amines were prepared by acidolytic deprotection. Title compound was also prepared by 'ring switching' transformation of N-Boc-pyrrolin-2(5H)-one with hydrazine hydrate. Hydrogenolytic deprotection of 5-(N-alkyl-N-Cbz-aminomethyl)pyrazolidine-3-ones followed by cyclisation with 1,1'-carbonyldiimidazole (CDI) gave two novel representatives of perhydroimidazo[1,5-b] pyrazole, which is an almost unexplored heterocyclic system. Amidation of 3-oxopyrazolidine-5-carboxylic acid gave the corresponding carboxamides in moderate yields. Diastereomeric non-racemic carboxamides obtained from (S)-AlaOMe and (S)-ProOMe were separated by MPLC.

Synthesis and in Vitro Evaluation of Monodisperse Amino-Functional Polyester Dendrimers with Rapid Degradability and Antibacterial Properties

Amine functional polymers, especially cationically charged, are interesting biomacromolecules for several reasons, including easy cell membrane entrance, their ability to escape endosomes through the proton sponge effect, spontaneous complexation and delivery of drugs and siRNA, and simple functionalization in aqueous solutions. Dendrimers, a subclass of precision polymers, are monodisperse and exhibit a large and exact number of peripheral end groups in relation to their size and have shown promise in drug delivery, biomedical imaging and as antiviral agents. In this work, hydroxyl functional dendrimers of generation 1 to 5 based on 2,2-bis(methylol)propionic acid (bis-MPA) were modified to bear 6 to 96 peripheral amino groups through esterification reactions with beta-alanine. All dendrimers were isolated in high yields and with remarkable monodispersity. This was successfully accomplished utilizing the present advantages of fluoride-promoted esterification (FPE) with imidazole-activated monomers. Straightforward postfunctionalization was conducted on a second generation amino-functional dendrimer with tetraethylene glycol through NHS-amidation and carbonyl diimidazole (CDI) activation to full conversion with short reaction times. Fast biodegradation of the dendrimers through loss of peripheral beta-alanine groups was observed and generational- and dose-dependent cytotoxicity was evaluated with a set of cell lines. An increase in neurotoxicity compared to hydroxyl-functional dendrimers was shown in neuronal cells, however, the dendrimers were slightly less neurotoxic than commercially available poly(amidoamine) dendrimers (PAMAMs). Additionally, their effect on bacteria was evaluated and the second generation dendrimer was found unique inhibiting the growth of Escherichia coli at physiological conditions while being nontoxic toward human cells. Finally, these results cement a robust and sustainable synthetic route to amino-functional polyester dendrimers with interesting chemical and biological properties.

Versatile functionalization platform of biporous poly(2-hydroxyethyl methacrylate)-based materials: Application in heterogeneous supported catalysis

This paper highlights the straightforward and versatile functionalization of biporous poly(2-hydroxyethyl methacrylate) (PHEMA)-based networks obtained from the double porogen templating approach, and their subsequent utilization as efficient catalytic supports in heterogeneous supported catalysis. Advantage of the availability of hydroxyl groups within the PHEMA-based frameworks was taken through chemical modification with carbonyl diimidazole. This key activation led to miscellaneous functionalization reactions of the materials via nucleophilic substitution or thiol-ene/thiol-yne “click” additions of functional organic molecules mainly containing amino or thiol groups. Further, in-situ generation and immobilization of gold nanoparticles (GNPs) on selected thiol- or amine-functionalized biporous frameworks allowed for the preparation of innovative GNP@PHEMA materials. The as-obtained hybrid frameworks could efficiently be used as supported catalysts in NaBH4-mediated reduction of 4-nitrophenol. The reusability of amine-bearing hybrid catalysts is proved over 5 successive 1h-cycles with stable yields around 90%.

1,1′-Carbonyldiimidazole and Mechanochemistry: A Shining Green Combination

The application of mechanical forces to enable a chemical reaction, also known as mechanochemistry, is actually experiencing an impressive renewal of interest among the chemists community. One major advantage of this approach in organic synthesis lies in the possibility to run essentially solvent-free reactions. In recent years, some research groups have combined these types of solvent-free processes with the use of an eco-friendly reagent: 1,1′-carbonyldiimidazole (CDI). Thus, a wide range of molecules, including carboxylic acids, amines, and alcohols, could react efficiently with CDI under ball-milling conditions. By providing a vast array of products (amides, carboxylic acids, esters, ureas, hydantoins, etc.) in an efficient, fast, user-friendly, and green manner, this approach presents all the prerequisites to soon become a first choice methodology for all organic chemists. The reasons for the past and future successes of this combination are summarized, analyzed, and discussed herein.

The First Zero-Length Mass Spectrometry-Cleavable Cross-Linker for Protein Structure Analysis.

Combining the properties of a zero-length cross-linker with cleavability by tandem mass spectrometry (MS/MS) poses great advantages for protein structure analysis using the cross-linking/MS approach. These include a reliable, automated data analysis and the possibility to obtain short-distance information of protein 3D-structures. We introduce 1,1'-carbonyldiimidazole (CDI) as an easy-to-use and commercially available, low-cost reagent that ideally fulfils these features. CDI bridges primary amines and hydroxy groups in proteins with the lowest possible spacer length of one carbonyl unit (ca. 2.6 Å). The cross-linking reaction can be conducted under physiological conditions in the pH range between 7.2 and 8. Urea and carbamate cross-linked products are cleaved upon collisional activation during MS/MS experiments generating characteristic product ions, greatly improving the unambiguous identification of cross-links. Our innovative analytical concept is exemplified and applied for bovine serum albumin (BSA), wild-type tumor suppressor p53, an intrinsically disordered protein, and retinal guanylyl cyclase activating protein-2 (GCAP-2).