Amide Coupling Research Articles

Synthesis ofSMA‐PEGhyperdispersant and its stabilization mechanism for carbon black

AbstractIn this paper, four comb hyperdispersants (SMA‐MPEGA) with different side chain lengths and side chain densities were prepared by the amide coupling reaction of styrene‐maleic anhydride (SMA) copolymer and methoxypolyethylene glycol amine (MPEGA). The dispersion behavior of SMA‐MPEGA on carbon black was investigated by rheology and water contact angle measurement. The combined technologies of transmission electron microscopy, digital light synthesis, zeta potential, surface tension and UV–Vis have been successfully used to reveal the stability mechanism of SMA‐MPEGA. The SMA3000‐MPEGA1000 with a molar ratio of styrene to maleic anhydride of 3:1 and the molecular weight of side chain PEG of 1000 has the optimum carbon black dispersion. The results of the effect of dispersant structure on its dispersion performance reveal that the stable adsorption of dispersant on the surface of carbon black is the key to obtaining a space or electrostatic repulsion stabilizing role.

Total Chemical Synthesis of Palmitoyl-Conjugated Insulin.

Commercially available insulins are manufactured by recombinant methods for the treatment of diabetes. Long-acting insulin drugs (e.g., detemir and degludec) are obtained by fatty acid conjugation at LysB29 ε-amine of insulin via acid-amide coupling. There are three amine groups in insulin, and they all react with fatty acids in alkaline conditions. Due to the lack of selectivity, such conjugation reactions produce non-desired byproducts. We designed and chemically synthesized a novel thiol-insulin scaffold (CysB29-insulin II), by replacing the LysB29 residue in insulin with the CysB29 residue. Then, we conjugated a fatty acid moiety (palmitic acid, C16) to CysB29-insulin II by a highly efficient and selective thiol-maleimide conjugation reaction. We obtained the target peptide (palmitoyl-insulin) rapidly within 5 min without significant byproducts. The palmitoyl-insulin is shown to be structurally similar to insulin and biologically active both in vitro and in vivo. Importantly, unlike native insulin, palmitoyl-insulin is slow and long-acting.

Porphyrin-Modified Beads for Use as Compensation Controls in Flow Cytometry

Flow cytometry can rapidly characterize and quantify diverse cell populations based on fluorescence measurements. The cells are first stained with one or more fluorescent reagents, each functionalized with a different fluorescent molecule (fluorophore) that binds to cells selectively based on their phenotypic characteristics, such as cell surface antigen expression. The intensity of fluorescence from each reagent bound to cells can be measured on the flow cytometer using channels that detect a specified range of wavelengths. When multiple fluorophores are used, the light from individual fluorophores often spills over into undesired detection channels, which requires a correction to the fluorescence intensity data in a process called compensation. Compensation control particles, typically polymer beads bound to a single fluorophore, are needed for each fluorophore used in a cell labeling experiment. Data from compensation particles from the flow cytometer are used to apply a correction to the fluorescence intensity measurements. This protocol describes the preparation and purification of polystyrene compensation beads covalently functionalized with the fluorescent reagent meso-tetra(4-carboxyphenyl) porphine (TCPP) and their application in flow cytometry compensation. In this work, amine-functionalized polystyrene beads were treated with TCPP and the amide coupling reagent EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride) at pH 6 and at room temperature for 16 h with agitation. The TCPP beads were isolated by centrifugation and resuspended in a pH 7 buffer for storage. TCPP-related particulates were observed as a byproduct. The number of these particulates could be reduced using an optional filtration protocol. The resultant TCPP beads were successfully used on a flow cytometer for compensation in experiments with human sputum cells labeled with multiple fluorophores. The TCPP beads proved stable following storage in a refrigerator for 300 days.

Small-Molecule Cdc25A Inhibitors Protect Neuronal Cells from Death Evoked by NGF Deprivation and 6-Hydroxydopamine.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases that are presently incurable. There have been reports of aberrant activation of cell cycle pathways in neurodegenerative diseases. Previously, we have found that Cdc25A is activated in models of neurodegenerative diseases, including AD and PD. In the present study, we have synthesized a small library of molecules targeting Cdc25A and tested their neuroprotective potential in cellular models of neurodegeneration. The Buchwald reaction and amide coupling were crucial steps in synthesizing the Cdc25A-targeting molecules. Several of these small-molecule inhibitors significantly prevented neuronal cell death induced by nerve growth factor (NGF) deprivation as well as 6-hydroxydopamine (6-OHDA) treatment. Lack of NGF signaling leads to neuron death during development and has been associated with AD pathogenesis. The NGF receptor TrkA has been reported to be downregulated at the early stages of AD, and its reduction is linked to cognitive failure. 6-OHDA, a PD mimic, is a highly oxidizable dopamine analogue that can be taken up by the dopamine transporters in catecholaminergic neurons and can induce cell death by reactive oxygen species (ROS) generation. Some of our newly synthesized molecules inhibit Cdc25A phosphatase activity, block loss of mitochondrial activity, and inhibit caspase-3 activation caused by NGF deprivation and 6-OHDA. Hence, it may be proposed that Cdc25A inhibition could be a therapeutic possibility for neurodegenerative diseases and these Cdc25A inhibitors could be effective treatments for AD and PD.

Development of Carbon Nanotube/Graphene- Based Alginate Interpenetrating Hydrogels for Removal of Antibiotic Pollutants.

The extensive use of pharmaceutical antibiotics in treatment of human and animal infections has resulted in growing concerns about antibiotic pollution worldwide. In this work a novel interpenetrating polymer network (IPN) hydrogel has been developed to function as an effective and non-selective adsorbent for various antibiotic pollutants in aqueous solution. This IPN hydrogel is made of multiple active components, including carbon nanotube (CNTs), graphene oxide (GO), and urea-modified sodium alginate (SA). It can be readily prepared through efficient carbodiimide-mediated amide coupling reaction followed by calcium chloride-induced alginate cross-linking. The structural properties, swellability, and thermal stability of this hydrogel have been investigated, while its adsorption properties towards an important antibiotic pollutant, tetracycline, was thoroughly characterized based on adsorption kinetic and isotherm analyses. With a BET surface area of 38.7 m2/g, the IPN hydrogel shows an excellent adsorption capacity of 84.28 ± 4.2 mg/g towards tetracycline in water, while the adsorption capacity is decreased by only 18% after four cycles of use, demonstrating very good reusability. Adsorptive performance in removing two other antibiotics, neomycin and erythromycin, has also been examined and compared. Overall, our studies disclose that this newly designed hybrid hydrogel is an effective and reusable adsorbent material for treating antibiotic pollution in the environment.

Synthesis of New 2‐(Pyridin‐4‐yl)‐1H‐imidazo[4,5‐b]pyridine Derivatives: In vitro Antibacterial and In silico Screening

AbstractA library of N‐substituted 2‐(pyridin‐4‐yl)‐1H‐imidazo[4,5‐b] pyridine‐7‐carboxamide and (2‐(pyridin‐4‐yl)‐1H‐imidazo[4,5‐b] pyridin‐7‐yl) methanamine analogues synthesized by a series of condensation, oxidation, acid amide coupling and reductive amination reactions. The structures of the compounds were confirmed by IR, 1H NMR, 13C NMR and ESI‐MM MS analysis data. The compounds were evaluated for their in vitro antibacterial activity. Antibacterial activity has been conducted on two Gram positive and one Gram negative bacteria. The results have exhibited that the nature of substrate has a profound effect on the biological activity. The biological activity has been conducted against Bacillus cereus, Klebsiella pneumonia and Staphylococcus aureus and the results were compared with the control Amikacin. Molecular docking and ADMET (absorption, distribution, metabolism, excretion and toxicity) studies have been conducted on the selected compounds to further rationalize the results.

Design, synthesis, and in silico-in vitro antimalarial evaluation of 1,2,3-triazole-linked dihydropyrimidinone quinoline hybrids

In response to the malaria parasite’s resistance towards quinoline-based antimalarial drugs, we have employed quinoline-containing compounds in combination with dihydropyrimidinone (DHPM) analogues as resistance reversal agents (RAs) and investigated their antimalarial activities based on DHPM’s resistance reversal abilities. The present study employed click chemistry to link DHPM and quinoline compounds which offered several synthetic advantages over the previously used amide coupling for the same hybrids. Among the synthesised compounds, 4 hybrids with the 7-chloroquinoline moiety showed antimalarial activity below 1 µM while compounds with the mefloquine moiety showed lower antimalarial activity than chloroquine (CQ) and the 7-chloroquinoline hybrids. Among the tested hybrids for the IC50 determination, four compounds displayed good antimalarial activity with increased sensitivity against the CQ-resistant K1 strain between 421 and 567 nM and showed higher activity between 138 and 245 nM against the NF54 CQ-sensitive strain, while three compounds have IC50 values greater than 5 µM. Additionally, in silico molecular docking and molecular dynamics studies were conducted to investigate the binding affinities of all the synthesised compounds as glutathione reductase protein competitive inhibitors. Further optimisation of the compound with the highest binding affinity generated 16 compounds with higher binding affinities than the flavine adenine dinucleotide (FAD) cofactor.

Synchronized delivery of dual-drugs for potentiating combination chemotherapy based on smart triple-responsive polymeric micelles

Here, we combined reversible addition-fragmentation chain transfer (RAFT) polymerization and amide coupling reaction to develop a novel drug-polymer conjugate using poly(AMA-co-IMMA)-b-poly(OEGMA) (termed as PAIPO) as nanocarriers. In order to enhance cellular uptake and obtain subsequent endo/lysosomal escape capacity, the dual-drugs-conjugated prodrug was then coupled with 2,3-dimethylmaleimide (DA) moieties and implanted with imidazolyl groups, respectively. Paclitaxel (PTX) was conjugated to PAIPO via 3,3′-dithiodipropionic acid (DPA) to construct a GSH-responsive moiety, while doxorubicin (DOX) was conjugated to PAIPO via 4-formyl benzoic acid to construct a pH-responsive moiety, which synergistically enabled a synchronized and precise drug delivery. The micelles self-assembled from DOX/PTX@PAIPODA showed an ideal average diameter (163.2–178.3 nm), contributing to passive targeting by the EPR effect. Moreover, a switch of the surface Zeta potential of micelles from steady negatively charged (− 9.74 ± 0.54 mV) at pH 7.4 to positively charged (+ 6.33 ± 1.25 mV) at pH 6.5, facilitated the long blood circulation and cellular endocytosis of micelles, respectively. More importantly, in vitro studies confirmed that DAM(DOXn/PTX) exhibited a strong synergism against tumor cells, and under slightly acidic conditions (pH 6.5), the combination index (CI) values for DAM(DOX1/PTX) on HeLa and Skov-3 cells were estimated to be 0.47 and 0.49 (previous to be 0.50 and 0.56 at pH 7.4), respectively. And in vivo results showed effective tumor accumulation potential, remarkable biosafety, and biocompatibility. Combined, such synchronized delivery approach based on multi-responsive micelles might potentiate the efficacy of combination chemotherapy in clinical cancer treatment.

Complexity-Building Photoinduced Cascade Involving Csp2-Csp3 Coupling of Aromatic Amides via [2 + 2] Reactivity of ESIPT-Generated o-Azaxylylenes.

A new mode for complexity-building photochemical cascades which offers experimentally simple transition metal-free intramolecular Csp2-Csp3 cross coupling of aromatic amides is attained via an unprecedented [2 + 2] reactivity of ESIPT-generated azaxylylenes. Coupled with short and straightforward postphotochemical modifications of the primary photoproducts, these cascades allow for a significant step-normalized growth of molecular complexity while accessing diverse and complex polyheterocyclic molecular architectures.

Design, Synthesis of Dioxopiperidinamide Derivatives by Amide Coupling Reaction and Study of Their Biological Activity

AbstractA series of fifteen dioxopiperidinamide derivatives synthesized and their spectra chemical data were reported. An alternative amide coupling reaction has been followed by using 3‐aminopiperidine‐2,6‐dione through amide bond functionalization between N‐Ethyl‐N′‐(3‐dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) and Hydroxybenzotriazole (HOBt). All the designed compounds were docked in to the active sites of 2 A73: Human Complement Component C3. All the docked compounds is favorable to make both hydrogen and hydrophobic interaction with amino acids located at the binding site. The most of potential compounds (E)‐N‐(2,6‐dioxopiperidin‐3‐yl)‐3‐(m‐tolyl)acrylamide (4 g), (E)‐3‐(4‐bromophenyl)‐N‐(2,6‐dioxopiperidin‐3‐yl)acrylamide (4 h) and N‐(2,6‐dioxopiperidin‐3‐yl)‐3‐methyl‐4‐oxo‐4,6,7,8,9,10‐hexahydrothieno [2′,3′:4,5]pyrimido[1,2‐a]azepine‐2‐carboxamide (7) studied for their anticancer activity on the THP‐1 cancer cells line. It was also further established their Anti‐inflammatory activity and Antioxidant activity with the comparable efficiency against those of clinically used drugs.

Large-Scale Amide Coupling in Aqueous Media: Process for the Production of Diazabicyclooctane β-Lactamase Inhibitors

Herein, the amide coupling of six primary amines with the sodium salt of diazabicyclooctane acid in an aqueous medium without an additional base/surfactant or organic solvent is described. The product was efficiently isolated from the reaction through simple filtration and recrystallized using hot water treatment as a swift and cost-effective process. The methodology was implemented on a kilogram scale to produce penultimate intermediates for synthesizing β-lactamase inhibitors such as zidebactam, relebactam, and nacubactam. The comparison of green metrics for several previously reported amide coupling methods was discussed. The developed procedure avoids using hazardous organic solvents and provides a simple isolation method at the operational level with high purity and efficiency.

Palladium-catalyzed coupling of amides and cyclopropanols for the synthesis of γ-diketones.

A palladium catalytic method has been developed for the coupling of amides and cyclopropanols to γ-diketones, through simultaneous C-N and C-C activation. Heteroatom ligand exchange and heteroatom-to-carbon ligation mode switching enable the achievement of molecular cross-coupling in an amide N-atom structural context-dependent manner, avoiding any stoichiometric organometallic reagent or base.

An interfacial toughening strategy for high stability 2D/3D perovskite X-ray detectors with a carbon nanotube thin film electrode.

Single-crystalline metal halide perovskite materials hold great promise for developing next-generation low-dose X-ray detection. To bring this new technology into reality, it is important to improve the durability of perovksite detectors by suppressing the well-known corrosion and ion diffusion problems at the perovskite/electrode interface. For imaging application, it is also imperative to develop new assembling approaches to realise non-planar interconnection between thick perovskite crystals and thin-film transistor (TFT) backplanes. Herein, a flexible and mechanically robust carbon nanotube (CNT) film was proposed to replace noble metal electrodes. The proposed CNT film, whose binder contains a carboxyl group, can form solid contact with a phenethylamine-based two-dimensional (2D) perovskite via amide coupling, thus toughening the perovskite-electrode interface. The resulting CNT/2D-3D perovskite detector shows an applaudable low dark current, high sensitivity, a low dose detection limit and excellent stability, retaining 98% of its initial sensitivity after storage for three months. Moreover, the flexible CNT films are also beneficial for making non-planar interconnection between thick perovskite crystals and TFT backplanes. The proposed flexible CNT thin film electrode thus provides a facile route towards realising a low-dose, high-resolution and highly stable perovskite X-ray detector.

Practical synthesis of allylic amines via nickel-catalysed multicomponent coupling of alkenes, aldehydes, and amides.

Molecules with an allylic amine motif provide access to important building blocks and versatile applications of biologically relevant chemical space. The need for diverse allylic amines requires the development of increasingly general and modular multicomponent reactions for allylic amine synthesis. Herein, we report an efficient catalytic multicomponent coupling reaction of simple alkenes, aldehydes, and amides by combining nickel catalysis and Lewis acid catalysis, thus providing a practical, environmentally friendly, and modular protocol to build architecturally complex and functionally diverse allylic amines in a single step. The method is remarkably simple, shows broad functional-group tolerance, and facilitates the synthesis of drug-like allylic amines that are not readily accessible by other methods. The utilization of accessible starting materials and inexpensive Ni(ii) salt as the alternative precatalyst offers a significant practical advantage. In addition, the practicality of the process was also demonstrated in an efficient, gram-scale preparation of the prostaglandin agonist.

Facile synthesis of chiral 2-functionalized tetrahydroquinolines via Pd/Cu-catalyzed cascade γ-C(sp3)–H arylation/C–N coupling of amides derived from amino acids and their derivatives

We successfully explored a one-pot strategy to synthesize valuable chiral 2-functionalized tetrahydroquinoline motifs through the precise modification of amides derived from commercially available natural amino acids.

Inconsistent hydrogen bond-mediated vibrational coupling of amide I.

Using infrared spectroscopy and density functional theory (DFT) calculations, we scrutinized an amide (dimethylformamide) as a "model" compound to interpret the interactions of amide 1 with different phenol derivatives (para-chlorophenol (PCP) and para-cresol (CP)) as "model guest molecules". We established the involvement of amide I in vibrational coupling with symmetric and asymmetric C[double bond, length as m-dash]C modes of different phenolic derivatives and how their coupling was dependent upon different guest aromatic phenolic compounds. Interestingly, substitution of phenol perturbed the pattern of vibrational coupling with amide I. The symmetric and asymmetric C[double bond, length as m-dash]C modes of PC were coupled significantly with amide 1. For PCP, the symmetric C[double bond, length as m-dash]C mode coupled significantly, but the asymmetric mode coupled negligibly, with amide I. Here, we reveal the nature of vibrational coupling based on the structure of a guest molecule hydrogen-bonded with amide I. Our conclusions could be valuable for depiction of the unusual dynamics of coupled amide-I modes as well as the dependency of vibrational coupling on altered factors.

A sustainable, efficient, and potentially cost-effective approach to the antimalarial drug candidate MMV688533.

A 6-step synthesis of the antimalarial drug candidate MMV688533 is reported. Key transformations carried out under aqueous micellar conditions include two Sonogashira couplings and amide bond formation. Compared with the first-generation manufacturing process reported by Sanofi, the current route featuresppm levels of palladium loading, less material input, less organic solvent, and no traditional amide coupling reagents. The overall yield is improved ten-fold, from 6.4% to 67%.

Repurposing amine and carboxylic acid building blocks with an automatable esterification reaction.

New methodologies to unite amines and carboxylic acids that complement the popular amide coupling can significantly expand accessible chemical space if they yield products distinct from the classic R-NHC(O)-R' amide arrangement. Here we have developed an amine-acid esterification reaction based on pyridinium salt activation of amine C-N bonds to create products of type R-OC(O)-R' upon reaction with alkyl and aryl carboxylic acids. The protocol is robust and facile as demonstrated by automation on open-source robotics.

A one-step base-free synthesis of N-arylamides via modified pivaloyl mixed anhydride mediated amide coupling.

Pivalic anhydride is shown to be an effective reagent for direct amidation of carboxylic acids with N-alkyl anilines. The only by-product of this reaction is nontoxic pivalic acid, which can be easily removed by aqueous workup. The reactions are conducted under mild conditions and found to be compatible with a range of carboxylic acids, including aromatic, heterocyclic, acrylic, and aliphatic carboxylic acids and amino acids generating the desired amides in short reaction times.

Development of a two-phase flow reaction system for DNA-encoded amide coupling

Synthesis platforms are of particular interest to DNA-encoded library (DEL) technologies to facilitate chemistry development, building block validation, and high-throughput library synthesis.