Amine Derivatives Research Articles

Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel C-17 Amine Derivatives Based on GSK3640254 as HIV-1 Maturation Inhibitors with Broad Spectrum Activity.

An investigation of the structure-activity relationships of a series of HIV-1 maturation inhibitors (MIs) based on GSK3640254 (4) was conducted by incorporating novel C-17 amine substituents to reduce the overall basicity of the resultant analogues. We found that replacement of the distal amine on the C-17 sidechain present in 4 with a tertiary alcohol in combination with either a heterocyclic ring system or a cyclohexyl ring substituted with polar groups provided potent wild-type HIV-1 MIs that also retained excellent potency against a T332S/V362I/prR41G variant, a laboratory strain that served as a surrogate to assess HIV-1 polymorphic virus coverage. Compound 26 exhibited broad-spectrum HIV-1 activity against an expanded panel of clinically relevant Gag polymorphic viruses and had the most desirable overall profile in this series of compounds. In pharmacokinetic studies, 26 had low clearance and exhibited 24 and 31% oral bioavailability in rats and dogs, respectively.

Synthesis and Biological Evaluation of Novel Pyrimidine Amine Derivatives Bearing Bicyclic Monoterpene Moieties.

A series of novel pinanyl pyrimidine amine derivatives (1e~1n) and camphoryl pyrimidine amine derivatives (2b~2f) bearing bicyclic monoterpene moieties were designed and synthesized from natural and renewable nopinone and camphor. All chemical structures of target compounds were characterized by 1H NMR, 13C NMR and HRMS spectra analyses, and the antimicrobial activities were evaluated. The results indicated that most compounds showed considerable antibacterial and antifungal activities against Klebsiella pneumoniae, Streptococcus pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Methicillin-Resistant Staphylococcus aureus (MRSA), Bacillus cereus and Candida albicans. Among them, 1f showed potent antibacterial activity against all tested bacteria, 1i exhibited excellent inhibition against Streptococcus pneumoniae (1 μg/mL) and Escherichia coli (1 μg/mL), which was better than the control drug amikacin (2 μg/mL). As to antifungal activity against Candida albicans (C. albicans), compound 1l showed comparable activity (16 μg/mL) to the control drug ketoconazole. Furthermore, five active compounds with better antimicrobial activities also showed anti-inflammatory potencies against mouse mononuclear macrophages leukemia cells (RAW). Especially, 1f (IC50 = 1.37 μM) and 2f (IC50 = 1.87μM) are more potent than the control drug aspirin (IC50 = 1.91 μM).

Intermolecular Redox-Neutral Carboamination of C–C Multiple Bonds Initiated by Transition-Metal-Catalyzed C–H Activation

Carboamination of readily available feedstock-like alkenes, alkynes, and allenes has proven to be an efficient and powerful tool for the synthesis of diverse and valuable amine derivatives of relevance to medicinal chemistry, biochemistry, and material science. Among these developed carboamination methodologies, the direct use of the C–H activation strategy to leverage the carboamination process is particularly attractive due to the ubiquity of such bonds in organic molecules. In this review, we provide an overview of the development of intermolecular carboamination across C–C π-bonds initiated by C–H activation in a redox-neutral and nonannulative manner, with an emphasis on synthetic and mechanistic aspects. In principle, this review summarized these reactions with a key feature of involving an initial C–H metalation followed by an intermolecular migratory insertion into π-bonds and terminated by an electrophilic amination quenching, and thus, it is ordered by the sources of C- and N-based functionalities and further divided by π-compounds.

FEATURES OF THE COURSE OF COVID-19 IN WOMEN WITH HYPERPROLACTINEMIA

The 2019 coronavirus pandemic is a major stressful event. In turn, stressful situations are triggers for the exacerbation of existing and activation of new diseases caused by a violation of the immune response in the human body and the development of inflammatory diseases. A stressful state causes the release of stress-mediated hormones, which in turn contributes to an increase in the level of PRL. Obviously, it is a closed circle. Therefore, the questions become relevant: 1. Can stress against the background of Covid-19 really cause an increase in the level of PRL? 2. Can Sovid-19 worsen the course of an already existing HP? Purpose: to conduct an analysis of available medical research on the peculiarities of the course of Covid-19 in women with HP, highlighting research on this topic in order to systematize new views on the diagnosis and treatment of Covid-19 against the background of already existing HP. Materials and methods. 10 articles from 2018 to 2022 with the keywords prolactin, hyperprolactinemia and Covid-19 were analyzed. Research results and their discussion. A review and analysis of a closed cohort study in which 30 men and 15 women participated and passed the Trier social stress test showed that PRL levels were significantly increased in response to a stressor [10], which could be the Covid-19 pandemic. In SARS-CoV-2, the defined receptor binding domain of the viral membrane protein uses angiotensin-converting enzyme 2 (ACE2) as a receptor for virus-host membrane fusion [2]. ACE2 regulates the activity of dopamine decarboxylase (DDC), which is responsible for the synthesis of dopamine and serotonin. Thus, SARS-CoV-2 disrupts the biosynthesis of dopamine, which leads to an increase in the level of PRL. With Covid-19, the expression of TLR4 and NF-κB is activated and increases the induction release of pro-inflammatory cytokines with the development of ALI, ARDS and cytokines with MOF. Conclusions Based on the studies described above, it can be concluded that Covid-19 inhibits the synthesis of dopamine and thus increases the level of prolactin. Also, prolactin can exhibit both
 immunostimulating and immunosuppressive, as well as pro-inflammatory and anti-inflammatory effects. Treatment with agonists of dopamine receptors can lead to deepening of depression in Covid-19. Treatment of hyperprolactinemia should be carried out with caution, because in critically ill patients who require personal support, the use of amine derivatives with DRA can cause additional vasospasm and, as a result, a rapid increase in blood pressure.

Pd-catalyzed functionalization of alkenes and alkynes using removable tethers

The palladium-catalyzed functionalization of alkenes is a versatile transformation in synthetic chemistry, but intermolecular processes often suffer from low reactivity and selectivity. Molecular tethers can be introduced to answer these challenges. They have been used successfully for decades, but their installation and removal normally required multi-step procedures. In this review, we will present progress in this area resulting in more efficient tethering processes. We will start with a brief overview of carbamate- and sulfone-based tethered functionalization of allylic alcohol and amine derivatives. Then the recent development of tethers that can be installed in situ on (homo)-allyl/propargyl amines or alcohols for double and triple bond functionalization will be described. The difunctionalization of alkenes and alkynes using trifluoro acetaldehyde based tethers developed by our group will be covered in more details. Finally, we will introduce the concept of tethers as catalytically formed chiral auxiliaries for asymmetric synthesis.

Pharmacological Significance of Synthetic Bioactive Thiazole Derivatives

Abstract: Thiazole and the related nuclei constitute one of the most significant moieties in the extensively emerging domain of heterocyclic compounds. The versatile nature of the thiazole nucleus can be determined as it is present in natural products like vitamin B1. Furthermore, its derivatives exhibit diverse biological activities, including antimicrobial, anticancer, antihistaminic, antioxidant, etc. They have also emerged as potent CNS agents and are primarily used in the treatment of various CNS disorders. The structure-activity relationship of various amine derivatives of ethylated thiazole demonstrates their use as potential agents in the treatment of melanoma, pigmentation as well as solar elastosis. Thiazole fused with different heterocyclic systems results in many novel derivatives with higher therapeutic activity. Benzothiazole and Thiazolopyrimidine have a distinct position in this regard. This review focuses on the central role of thiazole and its derivatives in current drug design, covering a broad spectrum of pharmacological activities associated with them.

Rational Design of Fluorescent/Colorimetric Chemosensors for Detecting Transition Metal Ions by Varying Functional Groups

In recent decades, concerns about increasing biological and environmental contamination have necessitated the development of chemosensors with high selectivity, sensitivity, and cost-effectiveness. In principle, the sensing performance can be affected by the functional group(s) of receptor, the charge of the metal ion(s), and the electron configuration of the sensing molecule(s)e and metal ion(s). Fine controlling of the substituents can influence the electron density of the receptor to enhance the binding affinity to metal ions, which is an effective way to improve the photophysical properties of the sensors. This review explores the effect of functional group modification on the performance of various chemosensors represented by Pt(dithiolene)-based complexes (2012–2021). Then, recently developed Schiff base chemosensors (2014–2021) are discussed. The Schiff base is a good platform for controlling electron configuration due to a facile synthesis of various organic structures (aldehyde or ketone groups with primary amine derivatives). The discussion focuses on the detection type, physicochemical and optical properties, and applications of these chemosensors.

Activation and Conversion of Molecular Nitrogen to the Precursor of Ammonia on Silicon Substituted Cyclo[18]Carbon: a DFT Design.

Recent synthesis of sp-hybridized cyclo[18]carbon allotrope has attracted immense curiosity. Since then, a generous amount of theoretical studies concerning aromaticity, adsorption, and spectra of the molecule have been performed. However, very few stuides have been carried out concerning its reactivities and catalytic behaviour. In this article, a DFT-based inquisition has been reported regarding the reactivity of Si substituted cyclo[18]carbon molecule towards molecular N2 . Results show that the Si substituted derivative is effective in producing adducts with molecular nitrogen. Charge calculations and IRC trapping methods indicate that only the Si center of C17 Si and its (HOMO-1) level participate in N2 addition. The N-adduct so formed, is then found to spontaneously react with molecular H2 . The addition of two H2 molecules to the activated nitrogen molecule to give respective amine derivatives have also been studied. The successful generation of the precursor of NH3 by C17 Si lays a clear emphasis on its potentiality.

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.

Efficiency of Functional Group Caging with Second-Generation Green- and Red-Light-Labile BODIPY Photoremovable Protecting Groups.

BODIPY-based photocages release substrates by excitation with wavelengths in the visible to near-IR regions. The recent development of more efficient BODIPY photocages spurred us to evaluate the scope and efficiency of these second-generation boron-methylated green-light and red-light-absorbing BODIPY photocages. Here, we show that these more photosensitive photocages release amine, alcohol, phenol, phosphate, halides, and carboxylic acid derivatives with much higher quantum yields than first-generation BODIPY photocages and excellent chemical yields. Chemical yields are near-quantitative for the release of all functional groups except the photorelease of amines, which react with concomitantly photogenerated singlet oxygen. In these cases, high chemical yields for photoreleased amines are restored by irradiation under an inert atmosphere. The photorelease quantum yield has a weak relationship with the leaving group pKa of the green-absorbing BODIPY photocages but little relationship with the red-absorbing derivatives, suggesting that factors other than leaving group quality impact the quantum yield. For the photorelease of alcohols, in all cases a carbonate linker (that loses CO2 upon photorelease) significantly increases both the quantum yield and the chemical yield compared to those for direct photorelease via the ether.

Copper-Catalyzed Boroaminomethylation of Olefins to γ-Boryl Amines with CO as C1 Source.

Boroaminomethylation of olefins is an efficient process to convert hydrocarbons directly into boron-, nitrogen-containing molecules. Such chemicals are a good handle for obtaining more complexed amine derivatives through the various transformations of organoboron. However, using simple and easily available CO as the C1 feedstock to achieve boroaminomethylation is still elusive. Here we report a copper-catalyzed boroaminomethylation of olefins with CO as the C1 source via the mechanism of a carbene insertion into the N-H bond. This method affords valuable γ-boryl amines from four inexpensive readily chemicals. The wide synthetic transformations of the γ-boryl amines demonstrates their utility. Notably, 13 C labeling studies revealed that the -CH2 -building block was derived from one molecule of CO.

Copper‐Catalyzed Boroaminomethylation of Olefins to γ‐Boryl Amines with CO as C1 Source

AbstractBoroaminomethylation of olefins is an efficient process to convert hydrocarbons directly into boron‐, nitrogen‐containing molecules. Such chemicals are a good handle for obtaining more complexed amine derivatives through the various transformations of organoboron. However, using simple and easily available CO as the C1 feedstock to achieve boroaminomethylation is still elusive. Here we report a copper‐catalyzed boroaminomethylation of olefins with CO as the C1 source via the mechanism of a carbene insertion into the N−H bond. This method affords valuable γ‐boryl amines from four inexpensive readily chemicals. The wide synthetic transformations of the γ‐boryl amines demonstrates their utility. Notably, 13C labeling studies revealed that the −CH2‐building block was derived from one molecule of CO.

Amines as Catalysts: Dynamic Features and Kinetic Control of Catalytic Asymmetric Chemical Transformations to Form C-C Bonds and Complex Molecules.

Carbonyl transformations involving enolates and/or enamines have been used for various types of bond-forming reactions. In this account, catalysts and catalyst systems that have amino acids or primary, secondary, and/or tertiary amines as key catalytic functional groups that we have developed to accelerate chemical transformations, including regio-, diastereo- and enantioselective reactions, are discussed. Our chemical transformation strategies and methods that use amine derivatives as catalysts are also discussed. As amines can have different functions depending on protonation and on the species formed during the catalysis (such as enamines and iminium ions), dynamics and kinetic controls are the keys for understanding the catalysis. Further, strategies that harness dynamic steps and kinetic control in amine-catalyzed reactions have enabled the synthesis of complex molecules in stereocontrolled manners. Understanding the dynamic features and the kinetic controls of the catalysis will further the design of the catalysts and the development of chemical transformation strategies and methods.

Biological Activity of Two Anticancer Pt Complexes with a Cyclohexylglycine Ligand against a Colon Cancer Cell Line: Theoretical and Experimental Study.

Because of their extraordinary ability to disrupt the natural structure of nucleic acids, metal complexes could be used in cancer therapy. In this study, cyclohexylglycine (HL) as a ligand and two new Pt complexes, [Pt(NH3)2(L)]NO3 (1) and [Pt(bipy)(L)]NO3 (2), were synthesized and characterized by elemental analysis, LC-MS, UV-vis spectrometry, FT-IR, 1H NMR spectroscopy, 13C NMR spectroscopy, 195Pt NMR spectroscopy, HPLC analysis, and single-crystal X-ray diffraction. Complex 2 crystallized in the orthorhombic Pbca space group, and density functional theory (DFT) was used to describe its structural parameters were described in detail. These complexes can be classified as oral medications and drug-like molecules based on a comparison of their absorption, distribution, metabolism, and excretion assessment. Quantum chemical descriptors (QCDs) were determined using DFT calculations to predict the tendency of DNA to approach these complexes. During the determination of the function of the metallodrug in DNA binding, the fluorescence data indicated that static quenching took place for all ligands and complexes with higher DNA binding affinity. CD and isothermal absorption studies indicate the presence of electrostatic and groove binding for the amine derivative and that DNA binds with the bipy moiety via groove binding. Furthermore, the interaction modes were determined using molecular docking to investigate the binding of these compounds with the target DNA molecule. According to docking investigations, binding energies of -5.7, -11.56, and -10.00 kcal/mol for HL and complexes 1 and 2, respectively, indicate partially electrostatic and groove binding. The anticancer activities of the Pt(II) complexes were tested against the HCT116 human colon cancer cell line, with IC50 values of 35.51 and 51.33 μM for 1 and 2, respectively, after 72 h. These values show that the inhibitory effect of complex 1 was better than those of 2 and carboplatin (IC50 = 51.94 μM).

Thermal crosslinking characteristics of dual-curable isocyanate blocked with methacrylate-functionalized amine derivatives for eco-friendly automotive clearcoats

A novel isocyanate blocked with an amine derivative blocking agent (2-(tert-butylamino) ethyl methacrylate, TBEMA) was designed as a thermal crosslinker for an eco-friendly automotive clearcoat system. New dual-curable blocked isocyanate (BITBEMA) was effectively deblocked at curing temperatures of 120 and 130 °C, which are lower than the conventional curing temperature of 150 °C. The deblocking features of BITBEMA were verified through experimental measurements and density functional theory simulations. The amine-based blocking agent with the methacrylate functionality directly participated in free radical polymerization with CC double bonds in the main resin (hydroxyl functionalized urethane methacrylate oligomer) during thermal curing, leading to enhanced crosslinking networks as well as reduced emissions of volatile organic compounds. The real-time crosslinking behaviors and mechanical properties of the clearcoat with BITBEMA were compared to those of clearcoats with mono-curable amine-based blocked isocyanate and a commercial crosslinker, confirming the excellent crosslinking characteristics of the dual-curable isocyanate crosslinker.

2,2′,3,3′-Tetrakis(4-bromophenyl)-6,6′-biquinoxaline based novel Donor–Acceptor–Acceptor−Donor (DAAD) Blue−Orange emitting molecules: Opto-electrochemical, AIE and theoretical investigation

A series of six novel donor‒acceptor‒acceptor‒donor (DAAD) based biquinoxaline amine derivatives 2–7 were obtained by employing palladium catalyzed Buchwald‒Hartwig coupling amination reaction. The synthesized compounds were characterized by spectroscopic and electrochemical techniques. The characteristic absorption spectra of dyes 2–7 display intramolecular charge transfer (ICT) transitions in the range of 415–461 nm. Dyes 2–7 show positive solvatochromism in emission and emit in blue−Orange region with emission maxima 492–598 nm in various solvents and neat solid film. Herein, dyes 2, 3 and 4 which possess intense emission in solid state were further studied for aggregation‒induced emission (AIE) effect in THF–water system due to the formation of nanoparticles, as confirmed by FEG‒SEM technique. The HOMO and LUMO energy levels for compounds 2–7 were measured by cyclic voltammetry (CV) and are found in the range of −4.96 to −5.35 eV and −3.33 to −3.46 eV which further correlated by density functional theory calculations. On the basis of comparable HOMO and LUMO energy levels to reported ambipolar materials, efficient solid state emission with good AIE and AIEE properties of the synthesized dyes signify their potential to be used as solid state emitters and ambipolar materials in opto−electronics.

Direct Reductive Arylation of Imines with Electron-Deficient (Hetero) Arenes via Electrosynthesis to Access Benzylic Amines.

In this paper, a direct access to benzylic amines from imines and electron-deficient (hetero) arenes via electrochemical radical-radical cross-coupling is described. The reaction has the characteristics of the wide range of substrates, excellent functional group tolerance, metal-free and highly atom-economical. The insensitivity to air and moisture makes this synthetic strategy more efficient for the construction of various benzylic amine derivatives.

Biodegradation of the pyrethroid cypermethrin by bacterial consortia collected from orange crops

Pyrethroids, such as cypermethrin (CYP), are widely employed in agriculture, promoting environmental pollution and the need for efficient decontamination methods. In this study, bacteria from orange crops were explored for CYP biodegradation. Among 40 tested bacterial strains, 20 grew in the presence of CYP and 19 performed statistically significant CYP biodegradation in 5 days (20.5%–97.8%). In addition, 3-phenoxybenzoic acid, the main metabolite from CYP, was quantified ranging from 1.1 mg.L−1 to 32.1 mg.L−1. The five most efficient strains, and consortia composed of 5, 10 and 20 bacteria biodegraded the CYP formulation as sole carbon source in phosphate buffer and in minimum mineral medium. Under optimized conditions determined employing Response Surface Methodology, Bacillus sp. CSA-1 and the consortium composed of 10 strains biodegraded 71.0% and 71.6% CYP in 24 h, respectively. Moreover, metabolite identification enabled the proposal of an extended biodegradation pathway with 29 identified compounds, including different new amide and amine derivatives that expanded the knowledge about the fate of this compound in the environment. Experiments of bioaugmentation in soil using Bacillus sp. CSA-1 and the consortium of 10 bacterial strains resulted in faster CYP biodegradation than natural attenuation, showing that the selection of efficient strains for composing a consortium is an interesting approach for bioremediation of pyrethroids.

Design and In-silico Molecular Docking of NMDA NR2B Receptor Antagonist and Pharmacokinetic Prediction of Some Piperazine Sulfonyl Amine Derivatives for Alzheimer’s Disease

Alzheimer's disease is a rare and progressive neurologic disease caused by degeneration of neurons within the brain that causes the brain to shrink (atrophy) and brain cells to die. In the US, approximately 5.5 million people are affected, and the prevalence worldwide is estimated to be as high as 24 million. Treatment is available to reduce the symptoms but no permanent cure. NMDA receptors play a crucial role in the treatment of Alzheimer's. Our aim and objective of the present work are to design some piperazine sulfonyl amine derivatives for treating Alzheimer's disease. To achieve this objective, we have docked the designed ligands with NMDA receptors. In our study, we have designed some piperazine sulfonyl amine derivatives, which were then subjected to virtual screening. The three-dimensional crystal structure of the selected protein NMDA receptor subunit NR2B (PDB Id: 3JPW) was retrieved from the RCSB Protein Data Bank (PDB). The ligands that showed low binding energy were further predicted for pharmacokinetic properties, and Lipinski's rule of 5 and the results are discussed. The final 19 compounds were used to develop a pharmacophore. The finalized 19 compounds were subjected to various in silico screening processes like drug-likeness, ADME properties and toxicity prediction. All 19 compounds exhibited good draggability nature, while ligands SE-B-15 and SE-B-12 were carcinogenic and SE-E-2 and SE-E-13 were prone to cause immunotoxicity. Ligands SE – C – 13 and SE – B – 2 exhibited good docking scores and best pharmacokinetic properties.

Design and synthesis of N-(1-(6-(substituted phenyl)-pyridazin-3-yl)-piperidine-3-yl)-amine derivatives as JMJD6 inhibitors

JMJD6 is a member of the JmjC domain-containing family and has been identified as a promising therapeutic target for treating estrogen-induced and triple-negative breast cancer. To develop novel anti-breast cancer agents, we synthesized a class of N-(1-(6-(substituted phenyl)-pyridazine-3-yl)-piperidine-3-yl)-amine derivatives as potential JMJD6 inhibitors. Among them, the anti-cancer compound A29 was an excellent JMJD6 binder (KD = 0.75 ± 0.08 μM). It could upregulate the mRNA and protein levels of p53 and its downstream effectors p21 and PUMA by inhibiting JMJD6. Besides, A29 displayed potent anti-proliferative activities against tested breast cancer cells by the induction of cell apoptosis and cell cycle arrest. Significantly, A29 also promoted a remarkable reduction in tumor growth, with a TGI value of 66.6% (50 mg/kg, i.p.). Taken together, our findings suggest that A29 is a potent JMJD6 inhibitor bearing a new scaffold acting as a promising drug candidate for the treatment of breast cancer.