Cyclic Amines Research Articles

A DFT/TDDFT Investigation on Fluorescence and Electronic Properties of Chromone Derivatives.

The development of quick and precise detection technologies for active compounds in vivo is critical for disease prevention, diagnosis and pathological investigation. The fluorescence signal of the fluorophore usually defines the probe's sensitivity to the chemical being examined. Many natural compounds containing flavone and isoflavone scaffolds exhibit a certain amount fluorescence, albeit with poor fluorescence quantum yields. Therefore, we used density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations to investigate the fluorescence characteristics of chromium-derived fluorophores in more depth. Different substituents are introduced at different positions of the chromone. As weak electron donor groups, alkyl and aromatic groups were discovered to have varying quantum yields on the fluorophore scaffold, and longer alkyl chains are favorable to enhance fluorescence quantum yield. In comparison to the amino group, substituted amino group can avoid group rotation, and the introduction of cyclic amines such as pyrrolidine and heterocyclic amines can improve optical characteristics. The electron-donating methoxy group at position 6 helps to increase the fluorescence quantum yield.

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer.

Carbonic anhydrases (CA), having Zn2+ metal atoms, are responsible for the catalysis of CO2 and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including brain, renal and pancreatic carcinomas. To cope with the lack of presence of a promising therapeutic agent against these cancers, searching for an efficient and suitable carbonic anhydrase inhibitor is crucial. In the current study, ten novel 3-ethylaniline hybrid imino-thiazolidinones were synthesized and characterized by FTIR, NMR (1H, 13C), and mass spectrometry. Synthesis was carried out by diethyl but-2-ynedioate cyclization and different acyl thiourea substitutions of 3-ethyl amine. The CA (II) enzyme inhibition profile for all synthesized derivatives was determined. It was observed that compound 6e demonstrated highest inhibition of CA-II with an IC50 value of 1.545 ± 0.016 µM. In order to explore the pharmacophoric properties and develop structure activity relationship, in silico screening was performed. In silico investigations included density functional theory (DFT) studies, pharmacophore-guided model development, molecular docking, molecular dynamic (MD) simulations, and prediction of drug likeness scores. DFT investigations provided insight into the electronic characteristics of compounds, while molecular docking determined the binding orientation of derivatives within the CA-II active site. Compounds 6a, 6e, and 6g had a reactive profile and generated stable protein-ligand interactions with respective docking scores of -6.12, -6.99, and -6.76 kcal/mol. MD simulations were used to evaluate the stability of the top-ranked complex. In addition, pharmacophore-guided modeling demonstrated that compound 6e produced the best pharmacophore model (HHAAARR) compared to standard brinzolamide. In vitro and in silico investigations anticipated that compound 6e would be an inhibitor of carbonic anhydrase II with high efficacy. Compound 6e may serve as a potential lead for future synthesis that can be investigated at the molecular level, and additional in vivo studies are strongly encouraged.

Multimatrix Variation Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry as a Tool for Determining the Bonding of Nitrogen Atoms in Alkaloids.

The reactivity of alkaloids in dehydrogenation was investigated using multimatrix variation matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) of over 20 different alkaloids with six matrices. The dehydrogenated molecular ions [M - H]+ generated by in-source decay were detected in the MALDI mass spectra of some types of alkaloids such as reserpine. The dehydrogenation proceeded at the cyclic tertiary amine rather than double-bonded nitrogen atoms and indole rings involved in the electron-delocalized systems. The stable protonated primary amines hindered dehydrogenation. The laser-induced dehydrogenation correlated with the chemical properties and structures of alkaloids. Alkaloids were classified into three types by the ratio of dehydrogenation by comparing the relative abundances of [M - H]+, [M]•+, and [M + H]+ ions in α-cyano-4-hydroxycinnamic acid and 5-formylsalicylic acid matrices. Structural isomers were also discriminated by this method of analyzing the three molecular ions' ratio using multimatrix variation MALDI-MS.

1,1-Enediamines as highly polarized olefin ligands

1,1-Enediamines were prepared by reaction of N,N-dimethylacetamide dimethyl acetal, Me2NC(OMe)2CH3, with the cyclic amines piperidine, homopiperidine, and morpholine. The resulting unsymmetric 1-morpholino-1-(dimethylamino)ethene (1) and the symmetric 1,1-dipiperidinoethene (2a), 1,1-dihomopiperidinoethene (2b) and 1,1-dimorpholinoethene (2c) were reacted with [(THT)AuCl] (THT = tetrahydrothiophene), trans-PdCl2(NCPh)2 and B(C6F5)3, respectively, to afford a series of gold, palladium, and boron complexes 3a-f. The new complexes were fully characterized by NMR spectroscopy and X-ray diffraction analysis, revealing their analogy with N-heterocyclic olefins (NHO) by η1-coordination through highly polarized C−C double bonds. Chloride abstraction from (1,1-dimorpholinoethene)gold(I)-chloride (3c) with AgPF6 in presence of another equivalent of free ligand afforded bis(1,1-dimorpholinoethene)gold(I)-hexafluorophosphate (4) as the first homoleptic bis(1,1-enediamine) metal complex.

A green aerobic Fe(lll) catalyzed base-free synthesis of 2-aminobenzothiazoles in water

An Fe(III) catalyzed, efficient methodology for the synthesis of 2-aminobenzothiazole derivatives in water was established. This mild, base-free, one-pot strategy showcases the reaction of readily available 2-bromophenyl isothiocyanate with a broad range of substituted amines such as aliphatic, aromatic, primary, secondary and cyclic amines under air. Notably, the reaction afforded the corresponding products with moderate to excellent yields in green conditions. The present optimization was found to be highly desirable for aliphatic amine substrates. Moreover, the catalyst could be successfully recovered and recycled for a minimum of 5 times without much loss in efficiency.

One-Pot Biocatalytic Synthesis of Primary, Secondary, and Tertiary Amines with Two Stereocenters from α,β-Unsaturated Ketones Using Alkyl-Ammonium Formate.

The efficient asymmetric catalytic synthesis of amines containing more than one stereogenic center is a current challenge. Here, we present a biocatalytic cascade that combines ene-reductases (EReds) with imine reductases/reductive aminases (IReds/RedAms) to enable the conversion of α,β-unsaturated ketones into primary, secondary, and tertiary amines containing two stereogenic centers in very high chemical purity (up to >99%), a diastereomeric ratio, and an enantiomeric ratio (up to >99.8:<0.2). Compared with previously reported strategies, our strategy could synthesize two, three, or even all four of the possible stereoisomers of the amine products while precluding the formation of side-products. Furthermore, ammonium or alkylammonium formate buffer could be used as the only additional reagent since it acted both as an amine donor and as a source of reducing equivalents. This was achieved through the implementation of an NADP-dependent formate dehydrogenase (FDH) for the in situ recycling of the NADPH coenzyme, thus leading to increased atom economy for this biocatalytic transformation. Finally, this dual-enzyme ERed/IRed cascade also exhibits a complementarity with the recently reported EneIRED enzymes for the synthesis of cyclic six-membered ring amines. The ERed/IRed method yielded trans-1,2 and cis-1,3 substituted cyclohexylamines in high optical purities, whereas the EneIRED method was reported to yield one cis-1,2 and one trans-1,3 enantiomer. As a proof of concept, when 3-methylcyclohex-2-en-1-one was converted into secondary and tertiary chiral amines with different amine donors, we could obtain all the four possible stereoisomer products. This result exemplifies the versatility of this method and its potential for future wider utilization in asymmetric synthesis by expanding the toolbox of currently available dehydrogenases via enzyme engineering and discovery.

2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli.

It was recently reported that 4-substituted picolinohydrazonamides carrying hydrophilic cyclic amines, such as morpholine and pyrrolidine, at the end of their thiosemicarbazide chain have potent antimycobacterial activity in vitro at concentrations below 1μg/ml. Here, two selected compounds, 2,4-disubstituted pyridine derivatives 11 and 15, revealed significant bactericidal activity against Mycobacterium tuberculosis localized intracellularly within human macrophages, as well as against biofilm-forming tubercle bacilli. Mutants were selected that were resistant to the investigated compounds at an efficiency similar to that identified in the presence of the first line antituberculosis drug rifampicin. The resistant mutants were viable in the presence of the tested compounds exclusively on solid media. Genome-wide sequencing of the mutants selected in the presence of compound 11 revealed the accumulation of nonsynonymous mutations in the mmpR5 gene encoding a transcriptional repressor of the MmpS5-MmpL5 efflux pump, whose upregulation has been associated with bedaquiline resistance. The depletion of MmpR5 in wild-type M. tuberculosis using CRISPR-Cas9 technology increased the resistance of this strain to compound 11. Mass spectrometry-based proteomics (LC-MS/MS) of wild-type tubercle bacilli growing in subinhibitory concentrations of compounds 11 or 15 revealed 15 overproduced proteins not detectable in the control cells, including virulence-related proteins.

Silver-Catalyzed Cascade Cyclization of Amino-NH-1,2,3-Triazoles with 2-Alkynylbenzaldehydes: An Access to Pentacyclic Fused Triazoles.

An operationally simple Ag(I)-catalyzed approach for the synthesis of isoquinoline and quinazoline fused 1,2,3-triazoles was developed by a condensation and amination cyclization cascade of amino-NH-1,2,3-triazoles with 2-alkynylbenzaldehydes involving three new C-N bond formations in one manipulation, in which the group of -NH of the triazole ring serves as a nucleophile to form the quinazoline skeleton. The efficient protocol can be applied to a variety of substrates containing a range of functional groups, delivering novel pentacyclic fused 1,2,3-triazoles in good-to-excellent yields.

Divergent C-H Amidations and Imidations by Tuning Electrochemical Reaction Potentials.

Electrochemical C-H functionalizations are attractive transformations, as they are capable of avoiding the use of transition metals, pre-oxidized precursors, or suprastoichiometric amounts of terminal oxidants. Herein an electrochemically tunable method was developed that enabled the divergent formation of cyclic amines or imines by applying different reaction potentials. Detailed cyclic voltammetry analyses, coupled with chronopotentiometry experiments, were carried out to provide insight into the mechanism, while atom economy was assessed through a paired electrolysis. Selective C-H amidations and imidations were achieved to afford five- to seven-membered sulfonamide motifs that could be employed for late-stage modifications.

Chromenes - A Novel Class of Heterocyclic Compounds: Recent Advancements and Future Directions.

Chromenes are an important class of oxygen-containing heterocyclic compounds with intriguing biological activity, a simple structure with mild adverse effects. Chromenes are abundantly found in nature in the form of alkaloids, tocopherols, flavone, and anthocyanins. The Chromene nucleus is an important moiety for the discovery of new drug candidates. Chromene derivatives have shown various pharmacological activities like antiviral, anticancer, anti-inflammatory, antitumour, antimicrobial, antiproliferative, anticholinesterase, EPR-1 (Effector cell Protease Receptor-1) antagonist and MAO (Mono-Amine Oxidase) inhibitors. In SAR (Structure Activity Relationship) studies with chromene nucleus, it was found that 4-aryl moiety, 3-cyano group, and 2-amino group are essential for the cytotoxic activity. Substitution at the 7th position with electron donating group enhances the pharmacological activity whereas the electron withdrawing group decreases the pharmacological activity. Structural modifications at the chromene ring, middle aliphatic portion, and terminal aromatic ring yielded more potential 5-HT1A (5-Hydroxytryptamine 1A) receptor affinity and antidiabetic activity. Chromenes with cyclic secondary amine and 4-hydroxy phenyl substituents yielded potent antimicrobial compounds. This review summarizes the importance of chromenes in rational drug design and the development of novel molecules with a variety of pharmacological activities.

Design and Screening of New Lead Compounds for Autism Based on QSAR Model and Molecular Docking Studies.

The purpose of the present study aims to develop a satisfactory model for predicting pro-social and pro-cognitive effects on azinesulfonamides of cyclic amine derivatives as potential antipsychotics. The three dimensional-quantitative structure affinity relationship (3D-QSAR) study was performed on a series of azinesulfonamides of cyclic amine derivative using comparative molecular similarity indices analysis (CoMSIA). The best statistical model of CoMSIA q2, r2, SEE and F values are 0.664, 0.973, 0.087, and 82.344, respectively. Based on the model contour maps and the highest activity structure of the 43rd compound, serial new structures were designed and the 43k1 compound was selected as the best structure. The dock results showed a good binding of 43k1 with the protein (PDB ID: 6A93). The QSAR model analysis of the contour maps can help us to provide guidelines for finding novel potential antipsychotics.

Unraveling the impact of hydrogen bonding and C‒H…π(CN) interactions in crystal engineering of cyclic aminobenzonitriles: A combined X-ray crystallographic and computational investigation

The essential role of organic crystals in drug development represents a significant research area and remains enduringly topical within the pharmaceutical industry. In the present study, four cyclic aminobenzonitriles 3a-d were prepared through the nucleophilic aromatic substitution reaction of 4-fluorobenzonitrile with various cyclic amines. The synthesized compounds were obtained in moderate to good yields and structurally characterized by FTIR, NMR spectroscopy, mass spectrometry and X-ray crystallography. The crystal packing of these compounds predominantly involves the use of hydrogen bonding interactions (C-H…N, C-H…S, C-H…O) and aromatic contacts (C-H…π(ring & CN), π…π) to govern the complex structural topology. These noncovalent interactions were further evaluated by molecular electrostatic potential (MEP) surface analysis and DFT energy calculations confirming the importance of π-stacking and CH…π interactions, either involving the arene or the π-system of the cyano groups. These interactions have been further characterized using the QTAIM/NCIplot computational tool.

Arabinogalactan propargyl ethers in the A3-coupling reaction with aldehydes and secondary cyclic amines

A family of novel pharmacologically prospective carbohydrate polymer aminomethylpropargyl derivatives has been synthesized by CuI-catalyzed A3-coupling reaction of arabinogalactan propargyl ethers with aldehydes and secondary amines in DMSO at 23–65 °С. The arabinogalactan derivatives bearing phenyl, pyridinе, and furan moieties in combination with piperidyne, pyrrolidyne, morpholine fragments are prepared in up to 95 % yield and 0.3–2.0 degree of substitution. Conversion of the propargyl groups of the starting arabinogalactan ethers reaches in most cases 80–100 %.The non-catalyzed aminoalkylation (96–100 °С, degree of substitution up to 1.1) of propargylated AG proceeds both at the ethynyl and hydroxy centers to afford mainly the products of C-substitution.Some of the synthesized compounds and their hydrochlorination products show the pronounced bacteriostatic activity with respect to Gram-negative microorganism.

Oxoammonium Salt-Promoted Multifunctionalization of Saturated Cyclic Amines Based On β-Oxo Cyclic Iminium Ion Intermediates.

Herein we describe a convenient method for multiple C(sp3)-H bond functionalization of saturated cyclic amines through oxoammonium salt-promoted oxidation to afford a β-oxo cyclic iminium ion as a key intermediate, followed by cascade addition with thiocyanate and diverse N-, O-, and S-containing nucleophiles in the green solvent and EtOH. Notably, chiral spiro azapolyheterocycles were prepared enantioselectively (>20:1 dr, up to 99% ee) when cysteine or serine esters were used as substrates. Moreover, the concise late-stage modification of several natural product derivatives was accomplished using this method.

A predictive group-contribution framework for the thermodynamic modelling of CO[formula omitted] absorption in cyclic amines, alkyl polyamines, alkanolamines and phase-change amines: New data and SAFT-[formula omitted] Mie parameters

A significant effort is under way to identify improved solvents for carbon dioxide (CO2) capture by chemisorption. We develop a predictive framework that is applicable to aqueous solvent + CO2 mixtures containing cyclic amines, alkyl polyamines, and alkanolamines. A number of the mixtures studied exhibit liquid–liquid phase separation, a behaviour that has shown promise in reducing the energetic cost of CO2 capture. The proposed framework is based on the SAFT-γ Mie group-contribution (GC) approach, in which chemical reactions are described via physical association models that allow a simpler, implicit, treatment of the chemical speciation characteristic of these mixtures. We use previously optimized group interaction parameters between some amine groups and water (Perdomo et al., 2021), and develop new group interactions for the cNH, cN, NH2, NH, N, cCHNH, and cCHN groups with CO2; a set of second-order group parameters are also developed to account for proximity effects in some alkanolamines. A combination of literature data and new experimental measurements for the absorption of CO2 in aqueous cyclohexylamine systems obtained in our current work, are used to develop and test the proposed models. The SAFT-γ Mie GC approach is used to predict the thermodynamics of selected mixtures, including ternary phase diagrams and mixing properties relevant in the context of CO2 capture. The current work constitutes a substantial extension of the range of aqueous amine-based solvents that can be modelled and thus offers the most comprehensive thermodynamically consistent platform to date to screen novel candidate solvents for CO2 capture.

Accelerated enzyme evolution for targeted C–H oxidation in cyclic amines

Accelerated enzyme evolution for targeted C–H oxidation in cyclic amines

Transition-Metal-Catalyzed Remote C–H Bond Functionalization of Cyclic Amines

AbstractC–H bond functionalization is one of the most effective strategies for the rapid synthesis of cyclic amines containing substituents on the ring, which are core structures of many bioactive molecules. However, it is much more challenging to perform this strategy on remote C–H bonds compared to the α-C–H bonds of cyclic amines. This graphical review aims to provide a concise overview on transition-metal-catalyzed methods for the remote C–H bond functionalization of cyclic amines. Examples are categorized and demonstrated according to mechanistic pathways that initiate the reactions of cyclic amine substrates. Where relevant, selected substrate scope and detailed reaction mechanisms are given.

Enantioselective oxidation of unactivated C–H bonds in cyclic amines by iterative docking-guided mutagenesis of P450BM3 (CYP102A1)

Selective oxidation of ring C–H bonds is an attractive route to functionalized cyclic amines, which are versatile intermediates in drug synthesis and important fragment molecules in drug discovery. Here we report a combined substrate and enzyme engineering approach to achieve enantioselective functionalization of all unactivated C–H bonds of azepane, azocane, 7-azabicyclo[2.2.1]heptane and 8-azaspiro[4.5]decane by cytochrome P450BM3 (CYP102A1). Different N-modifying groups provide product diversity at high enantioselectivity (up to 99% e.e.) from a panel of just 48 variants of P450BM3. Substrate docking into molecular-dynamics-simulated structures of enzyme variants is shown to be useful for designing mutations to increase enantioselectivity by disfavouring binding poses leading to the unwanted enantiomer, and to increase enzymatic activity by disfavouring non-productive poses from ten or so variants per generation. The synthetic application of remote C–H activation within cyclic amines is exemplified by the synthesis of anisodamine via enantioselective hydroxylation of N-Boc-nortropinone.

Air monitoring of tire-derived chemicals in global megacities using passive samplers

Pollution from vehicle tires has received world-wide research attention due to its ubiquity and toxicity. In this study, we measured various tire-derived contaminants semi-quantitatively in archived extracts of passive air samplers deployed in 18 major cities that comprise the Global Atmospheric Passive Sampling (GAPS) Network (GAPS-Megacities). Analysis was done on archived samples, which represent one-time weighted passive air samples from each of the 18 monitoring sites. The target analytes included cyclic amines, benzotriazoles, benzothiazoles, and p-phenylenediamine (PPD) derivatives. Of the analyzed tire-derived contaminants, diphenylguanidine was the most frequently detected analyte across the globe, with estimated concentrations ranging from 45.0 pg/m3 in Beijing, China to 199 pg/m3 in Kolkata, India. The estimated concentrations of 6PPD-quinone and total benzothiazoles (including benzothiazole, 2-methylthio-benzothiazole, 2-methyl-benzothiazole, 2-hydroxy-benzothiazole) peaked in the Latin American and the Caribbean region at 1 pg/m3 and 100 pg/m3, respectively. In addition, other known tire-derived compounds, such as hexa(methoxymethyl)melamine, phenylguanidine, and various transformation products of 6PPD, were also monitored and characterized semi-quantitatively or qualitatively. This study presents some of the earliest data on airborne concentrations of chemicals associated with tire-wear and shows that passive sampling is a viable techniquefor monitoring airborne tire-wear contamination. Due to the presence of many tire-derived contaminants in urban air across the globe as highlighted by this study, there is a need to determine the associated exposure and toxicity of these chemicals to humans.

Metal‐Free Aminomethylation of Pyrazolones: Direct Access to 4‐Aminomethylated Pyrazolones

AbstractA metal‐free aminomethylation of pyrazolones is accomplished with cyclic amines such as morpholine and piperazine analogues in the presence of (diacetoxyiodo)benzene at ambient temperature. Various sensitive functional groups can be compatible under the reaction conditions. Preliminary mechanistic investigation reveals that morpholine or piperazine analogues are likely to be the source of methylene group. This method provides a straightforward route for the preparation of 4‐aminomethylated pyrazolone derivatives under mild conditions.