Synthesis of novel aryl-substituted 2-aminopyridine derivatives by the cascade reaction of 1,1-enediamines with vinamidinium salts to develop novel anti-Alzheimer agents.

Alzheimer's disease (AD), a severe neurodegenerative disorder, imposes socioeconomic burdens and necessitates innovative therapeutic strategies. Current therapeutic interventions are limited and underscore the need for novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes implicated in the pathogenesis of AD. In this study, we report a novel synthetic strategy for the generation of 2-aminopyridine derivatives via a two-component reaction converging aryl vinamidinium salts with 1,1-enediamines (EDAMs) in a dimethyl sulfoxide (DMSO) solvent system, catalyzed by triethylamine (Et3N). The protocol introduces a rapid, efficient, and scalable synthetic pathway, achieving good to excellent yields while maintaining simplistic workup procedures. Seventeen derivatives were synthesized and subsequently screened for their inhibitory activity against AChE and BChE. The most potent derivative, 3m, exhibited an IC50 value of 34.81 ± 3.71 µM against AChE and 20.66 ± 1.01 µM against BChE compared to positive control donepezil with an IC50 value of 0.079 ± 0.05 µM against AChE and 10.6 ± 2.1 µM against BChE. Also, detailed kinetic studies were undertaken to elucidate their modes of enzymatic inhibition of the most potent compounds against both AChE and BChE. The promising compound was then subjected to molecular docking and dynamics simulations, revealing significant binding affinities and favorable interaction profiles against AChE and BChE. The in silico ADMET assessments further determined the drug-like properties of 3m, suggesting it as a promising candidate for further pre-clinical development.

Investigating catalytic pathways: a comparative review of homogeneous and heterogeneous catalysis for 3-aroylimidazo[1,2-a]pyridine synthesis.

3-aroylimidazo[1,2-a]pyridines represent a class of derivatives in the imidazo[1,2-a]pyridine family known for their important biological and pharmaceutical activities. Consequently, various methodologies have been designed to simplify the synthesis of this structure, with an emphasis on the use of cost-effective starting materials and environmentally friendly protocols. All the methods developed in recent years (from 2016 to 2023) rely on homogeneous or heterogeneous catalysts. Therefore, we aim to perform a comparative analysis between these two approaches, elucidating their respective advantages and limitations. The first part of this work focuses on techniques employing homogeneous catalysts, followed by the next section devoted to heterogeneous catalysts. This comprehensive review should be of substantial interest to researchers in the fields of organic and medicinal chemistry, as it provides a valuable resource for their research.

Sequencing-based analysis of RNA structures in living cells with 2A3 via SHAPE-MaP.

Chemical probing of RNA 2'-hydroxyl groups by selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) is a rapid and powerful approach for querying RNA structures in living cells. At reverse transcription, sites of chemical modification can be encoded as mutations in the cDNA, a process called mutational profiling (MaP), enabling their detection via high-throughput sequencing. This chapter describes how to synthesize the SHAPE probe 2-aminopyridine-3-carboxylic acid imidazolide (2A3), how to use it to probe RNA structures in living bacteria, and how to generate Illumina-compatible SHAPE-MaP sequencing libraries. The protocol further describes data analysis using the RNA Framework, from raw sequencing data processing to experimentally-driven RNA secondary structure model generation.

Synthesis, density functional theory and kinetic studies of aminopyridine based α-glucosidase inhibitors.

Aims: The current study aimed to develop new thiourea derivatives as potential α-glucosidase inhibitors for the management of hyperglycemia in patients of Type 2 diabetes, with a focus on identifying safer and more effective antidiabetic agents. Materials & methods: New thiourea derivatives (1-16) were synthesized through single-step chemical transformation and evaluated for in vitro α-glucosidase inhibition. Kinetic studies identified the mode of inhibition, free energy and type of interactions were analyzed through density functional theory and molecular docking. Results & conclusion: Compound 5 was identified as the most potent, noncompetitive and noncytotoxic inhibitor of α-glucosidase enzyme with a half-maximal inhibitory concentration of 24.62 ± 0.94 µM. Computational studies reinforce experimental results, demonstrating significant enzyme interactions via hydrophobic and π-π stacking forces.

Discovery of novel 2-aminopyridine derivatives as ROS1 and ALK dual inhibitors to combat drug-resistant mutants including ROS1G2032R and ALKG1202R.

Clinical treatment by FDA-approved ROS1/ALK inhibitor Crizotinib significantly improved the therapeutic outcomes. However, the emergence of drug resistance, especially driven by acquired mutations, have become an inevitable problem and worsened the clinical effects of Crizotinib. To combat drug resistance, some novel 2-aminopyridine derivatives were designed rationally based on molecular simulation, then synthesised and subjected to biological test. The preferred spiro derivative C01 exhibited remarkable activity against CD74-ROS1G2032R cell with an IC50 value of 42.3 nM, which was about 30-fold more potent than Crizotinib. Moreover, C01 also potently inhibited enzymatic activity against clinically Crizotinib-resistant ALKG1202R, harbouring a 10-fold potency superior to Crizotinib. Furthermore, molecular dynamic disclosed that introducing the spiro group could reduce the steric hindrance with bulky side chain (Arginine) in solvent region of ROS1G2032R, which explained the sensitivity of C01 to drug-resistant mutant. These results indicated a path forward for the generation of anti Crizotinib-resistant ROS1/ALK dual inhibitors.

Simple Synthetic Approach to N-(Pyridin-2-yl)imidates from Nitrostyrenes and 2-Aminopyridines via the N-(Pyridin-2-yl)iminonitriles as Intermediates.

A facile, green, synthetic protocol of several substituted N-(pyridin-2-yl)imidates from nitrostyrenes and 2-aminopyridines via the corresponding N-(pyridin-2-yl)iminonitriles as intermediates is reported. The reaction process involved the in situ formation of the corresponding α-iminontriles under heterogeneous Lewis acid catalysis in the presence of Al2O3. Subsequently, α-iminonitriles were selectively transformed into the desired N-(pyridin-2-yl)imidates under ambient conditions and in the presence of Cs2CO3 in alcoholic media. Under these conditions, 1,2- and 1,3-propanediols also led to the corresponding mono-substituted imidates at room temperature. The present synthetic protocol was also developed on one mmol scale, providing access to this important scaffold. A preliminary synthetic application of the present N-(pyridin-2-yl)imidates was carried out for their facile conversion into the N-heterocycles 2-(4-chlorophenyl)-4,5-dihydro-1H-imidazole and 2-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine in the presence of the corresponding ethylenediamine and 1,3-diaminopropane.

Room temperature phosphorescence of 2-aminopyridine with direct triplet state excitation.

Phosphorescence emission at room temperature has been observed from 2-Aminopyridyne (2APi) embedded in poly (vinyl alcohol) (PVA) films. The gated emission with UV excitation at 305 nm results in a residual delayed fluorescence at around 350 nm and a broad phosphorescence spectrum with a maximum of around 500 nm. The phosphorescence excitation spectrum of 2APi - doped PVA film differs from the absorption spectrum in the long-wavelength part, showing a band at about 400-450 nm. The phosphorescence spectrum measured with a blue (420 nm) excitation closely resembles the spectrum measured with 305 nm excitation. Whereas the phosphorescence anisotropy measured with UV excitation is low and negative, with the blue excitation, the anisotropy is high and positive. The phosphorescence lifetimes (a fraction of a millisecond) are similar for UV and blue excitations. Both phosphorescence emissions with either UV or blue excitation strongly depend on temperature.

Design, synthesis and in vitro biological evaluation of 2-aminopyridine derivatives as novel PI3Kδ inhibitors for hematological cancer.

Phosphoinositide-3-kinase (PI3K) involves in regulation of proliferation, cell cycle, and apoptosis, and is overexpressed in most of human malignant tumors. Therefore, the development of PI3K inhibitors has attracted great interest in tumor treatment. In this study, we designed and synthesized a series of 2-aminopyridine derivatives via a bioisosterism strategy. Among them, compound MR3278 showed superior PI3Kδ inhibitory activity (IC50 = 30 nM), as well as higher inhibitory activity to most of AML cells (e.g., MOLM-16 and Mv-4-11 cells with IC50 values of 2.6 µM and 3.7 µM, respectively) than Idelalisib. Further cell studies indicated that MR3278 could induce G2/M phase arrests and cell apoptosis of Mv-4-11 cells via PI3K dependent pathway in a dose dependent manner. In addition, in silico physicochemical and ADMET evaluation revealed its drug-like properties with satisfactory toxicity profiles. These results indicate that MR3278 can be identified as a promising new lead compound to the current PI3Kδ inhibitor and is worthy of further profiling.

Efficient Synthesis of 2-Aminopyridine Derivatives: Antibacterial Activity Assessment and Molecular Docking Studies.

A new and suitable multicomponent one-pot reaction was developed for the synthesis of 2-amino-3-cyanopyridine derivatives. BACKGROUND: This synthesis was demonstrated by the efficient and easy access to a variety of substituted 2-aminopyridines using enaminones as key precursors under solvent-free conditions. METHODS: A range of spectroscopic techniques was used to determine and confirm the chemical structures (FTIR, 1H NMR, 13C NMR). The antimicrobial potency of synthesized compounds (2a-d) was tested using disk diffusion assays, and the Minimum Inhibitory Concentration (MIC) for the active compounds was determined against a panel of microorganisms, including Gram-positive and Gram-negative bacteria and yeasts. Moreover, a docking analysis was conducted by Molecular Operating Environment (MOE) software to provide supplementary information about the potential, as well as an ADME-T prediction to describe the pharmacokinetic properties of the best compound and its toxicity. RESULTS: The results of the antimicrobial activity indicated that compound 2c showed the highest activity against Gram-positive bacteria, particularly S. aureus and B. subtilis whose MIC values were 0.039 ± 0.000 µg·mL-1. The results of the theoretical study of compound 2c were in line with the experimental data and exhibited excellent antibacterial potential. CONCLUSIONS: On the basis of the obtained results, compound 2c can be used as an antibacterial agent model with high antibacterial potency.

Synthesis of Highly Substituted 2-Aminopyridines with Vinyl Azides, Isonitriles, and Ketones.

We developed a facile, efficient method for synthesizing highly substituted 2-aminopyridines from unstable vinyl carbodiimides generated in situ in a one-pot transformation. A series of novel highly substituted 3-functionalized 2-aminopyridines were produced in good yields. Reaction mechanism studies, which included control experiments and density-functional theory (DFT) calculations, demonstrated that Rh and potassium carbonate played key roles in the cyclization step.

The influence of bioactive glyoxylate bearing Schiff base on antifungal and antioxidant activities to chitosan quaternary ammonium salts.

In this study, to investigate the influence of glyoxylate bearing Schiff base on bioactivity to chitosan quaternary ammonium salts, different chitosan derivatives were synthesized by ion exchange of glyoxylate bearing Schiff base with chitosan quaternary ammonium salts (TMCI and HACC). For this purpose, glyoxylate was prepared by Schiff base reaction of glyoxylic acid and amino heterocycles and it was further ionization to substitute iodide ions and chloride ions. After structural characterization by FTIR and 1H NMR, the antifungal and antioxidant activities were measured. Results indicated that glyoxylate bearing Schiff base could improve the bioactivity of TMCI and HACC obviously. Specifically, anionic TMCI with Schiff base of amino pyridines possessed best antioxidant activity >92.40% at 1.6 mg/mL against DPPH radicals. Meanwhile, they showed antifungal activity >84.88% at 1.0 mg/mL against G. cingulate. Furthermore, the cytotoxicity was evaluated, and all samples showed good cell viability >80.14% at 1000 µg/mL.

Cytotoxic Evaluation and Molecular Docking Studies of Aminopyridine Derivatives as Potential Anticancer Agents.

BACKGROUND: The development of resistance to available anticancer drugs is increasingly becoming a major challenge and new chemical entities could be unveiled to compensate for this therapeutic failure. OBJECTIVES: The current study demonstrated whether N-protected and deprotected amino acid derivatives of 2- aminopyridine could attenuate tumor development using colorectal cancer cell lines. METHODS: Biological assays were performed to investigate the anticancer potential of synthesized compounds. The in silico ADME profiling and docking studies were also performed by docking the designed compounds against the active binding site of beta-catenin (CTNNB1) to analyze the binding mode of these compounds. Four derivatives 4a, 4b, 4c, and 4d were selected for investigation of in vitro anticancer potential using colorectal cancer cell line HCT 116. The anti-tumor activities of synthesized compounds were further validated by evaluating the inhibitory effects of these compounds on the target protein beta-catenin through in vitro enzyme inhibitory assay. RESULTS: The docking analysis revealed favorable binding energies and interactions with the target proteins. The in vitro MTT assay on colorectal cancer cell line HCT 116 and HT29 revealed potential anti-tumor activities with an IC50 range of 3.7-8.1µM and 3.27-7.7 µM, respectively. The inhibitory properties of these compounds on the concentration of beta-catenin by ELISA revealed significant percent inhibition of target protein at 100 µg/ml. CONCLUSION: In conclusion, the synthesized compounds showed significant anti-tumor activities both in silico and in vitro, having potential for further investigating its role in colorectal cancer.

A BODIPY based probe for the reversible "turn on" detection of Au(III) ions.

A new "turn on" fluorescent probe for the rapid and selective detection of Au3+ ions over other metal ions was developed. The probe design was constructed on a BODIPY-2-aminopyridine skeleton showing a weak fluorescence emission signal which increased substantially after the coordination of Au3+ ions. The probe displayed remarkable sensing performances such as a low limit of detection (17 nM), a short response time (<1 min), and ability in a wide range of pH's (6-11). The designed probe was found to have 2:1 coordination stoichiometry according to Job's plot analysis and most importantly to interact reversibly with Au3+ ions.

Tissue N-Glycan Analysis Using LC-MS, MS/MS, and MSn.

Tissue glycans usually contain various structures, from simple to highly complicated, in different quantities. N-Glycans are particularly heterogeneous, with up to pentaantennary structures, different branch sequences, and several isomeric structures. 2-Aminopyridine (PA) tagging on released N-glycans is useful for separating isomers and to quantitatively analyze both the major and minor glycan structures in tissues using reversed-phase liquid chromatography (LC)-mass spectrometry (MS) and MS/MS analysis. Because the structural differences of PA-N-glycans influence their retention on a reversed-phase C18 column, it is easy to deduce the core structure, including core Fuc and bisecting GlcNAc as well as the branching pattern of each PA-N-glycan, based on the results of elution position, full MS, and MS/MS analysis. If more detailed structural analysis is required, combining sequential exoglycosidase digestions, sialic acid linkage-specific alkylamidation (SALSA), and/or SALSA/permethylation is useful for determining glycosidic linkages of branches. This article includes detailed protocols for the preparation of N-glycans released from glycoproteins/glycopeptides by glycoamidase F or hydrazinolysis, PA-tagging of N-glycans, fractionation with anion-exchange chromatography, and chemical or enzymatic modifications of PA-N-glycans, as well as reversed-phase LC-MS, MS/MS, and MSn analysis of PA-N-glycans from tissues. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Preparation of released N-glycans from tissue samples using glycoamidase F Alternate Protocol: Preparation of released N-glycans from tissue samples by hydrazinolysis Basic Protocol 2: PA-tagging of N-glycans and sample cleanup Support Protocol 1: Monitoring of PA-N-glycans using normal-phase HPLC Basic Protocol 3: Anion-exchange chromatography of PA-N-glycans Basic Protocol 4: Sequential exoglycosidase digestions Basic Protocol 5: Determination of Sia-linkages by SALSA Support Protocol 2: Cotton-HILIC solid-phase extraction to remove reagents for alkylamidation Basic Protocol 6: Sequential modifications of glycans with SALSA and permethylation Basic Protocol 7: LC-MS and MS/MS analysis of PA-N-glycans (before permethylation) Basic Protocol 8: LC-MS, MS/MS, and MSn analysis of PA-N-glycans (after permethylation).

Studying the Binding Modes of Novel 2-Aminopyridine Derivatives as Effective and Selective c-Met Kinase Type 1 Inhibitors Using Molecular Modeling Approaches.

The mesenchymal epithelial cell transforming factor c-Met, encoded by c-Met proto-oncogene and known as a high-affinity receptor for Hepatocyte Growth Factor (HGF), is one of the receptor tyrosine kinases (RTKs) members. The HGF/c-Met signaling pathway has close correlation with tumor growth, invasion and metastasis. Thus, c-Met kinase has emerged as a prominent therapeutic target for cancer drug discovery. Recently a series of novel 2-aminopyridine derivatives targeting c-Met kinase with high biological activity were reported. In this study, 3D quantitative structure-activity relationship (QSAR), molecular docking and molecular dynamics simulations (MD) were employed to research the binding modes of these inhibitors.The results show that both the atom-based and docking-based CoMFA (Q2 = 0.596, R2 = 0.950 in atom-based model and Q2 = 0.563, R2 = 0.985 in docking-based model) and CoMSIA (Q2 = 0.646, R2 = 0.931 in atom-based model and Q2 = 0.568, R2 = 0.983 in docking-based model) models own satisfactory performance with good reliabilities and powerful external predictabilities. Molecular docking study suggests that Tyr1230 and Arg1208 might be the key residues, and electrostatic and hydrogen bond interactions were shown to be vital to the activity, concordance with QSAR analysis. Then MD simulation was performed to further explore the binding mode of the most potent inhibitor. The obtained results provide important references for further rational design of c-Met Kinase type I inhibitors.

New synthetic chitosan derivatives bearing benzenoid/heterocyclic moieties with enhanced antioxidant and antifungal activities.

In this paper, several novel chitosan derivatives bearing benzenoid / heterocyclic moieties were synthesized via introducing aminobenzene and heterocyclic compounds onto carboxymethyl chitosan. The specific structures of chitosan derivatives were confirmed by FTIR, 1H NMR, and elemental analysis. Meanwhile, the antioxidant efficiencies of chitosan derivatives were assayed in vitro. In particular, all chitosan derivatives showed significant improvement in superoxide-radical scavenging activity and DPPH radical scavenging activity. Their antifungal activities against two plant pathogenic fungi (Colletotrichum lagenarium and Phomopsis asparagi) were estimated in vitro by hyphal measurement, and all products exhibited excellent antifungal activity. Besides, the cytotoxicity of them was also measured by CCK-8 in vitro on L929 cells, and all samples showed low cytotoxicity. The good biocompatibility and enhanced biological activity of new synthetic chitosan derivatives might be obvious advantages, while applied in wide range of applications as antifungal agents or antioxidants in food, medicine, cosmetics, and other fields.

Diversity-Oriented Synthesis of Thiazolidine-2-imines via Microwave-Assisted One-Pot, Telescopic Approach and Its Interaction with Biomacromolecules.

In this work, a one-pot, telescopic approach is described for the combinatorial library of thiazolidine-2-imines. The synthetic manipulation proceeds smoothly via the reaction of 2-aminopyridine/pyrazine/pyrimidine with substituted isothiocyanates followed by base catalyzed ring closure with 1,2-dibromoethane to obtain thiazolidine-2-imines with broad substrate scope and high functional group tolerance. The synthetic strategy merges well with the thiourea formation followed by base catalyzed ring closure reaction for the thiazolidine-2-imine synthesis in a more modular and straightforward approach. The synthetic procedure reported herein represents a cleaner route toward thiazolidine-2-imines as compared to traditional methodologies. Moreover, the biological significance of combinatorially synthesized thiazolidin-2-imines has been investigated for their use as possible inhibitors for acetyl cholinesterase through molecular docking studies.

Analysis of 2-aminopyridine labeled glycans by dual-mode online solid phase extraction for hydrophilic interaction and reversed-phase liquid chromatography.

Quantitative analysis of glycans released from glycoproteins using high-performance liquid chromatography (HPLC) requires fluorescent tag labeling to enhance sensitivity and selectivity. However, the methods required to remove large amounts of excess labeling reagents from the reaction mixture are time-consuming. Furthermore, these methods, including solvent extraction and solid phase extraction (SPE), often impair quantitative analysis. Here, we developed an online sample cleanup procedure for HPLC analysis of 2-aminopyridine (AP)-labeled glycans using a six-port/two-way valve and two small columns: one packed with a strong cation exchange resin (SCX) and the other comprising ODS silica gel. AP-labeled glycans delivered from an injection port were separated from excess AP by passing through an SCX column (4.6 mm i.d., 1 cm long) regulated to 40°C. The AP-labeled glycans were trapped on an ODS column (4.6 mm i.d., 1 cm long) to further separate them from inorganic contaminants. By changing the valve position after 2 min to connect the ODS column to an analysis column, AP-labeled glycans trapped in the ODS column were eluted with an acetonitrile-containing eluent followed by hydrophilic interaction liquid chromatography (HILIC) separation on an amide column or reversed-phase mode separation on a C30 column. This method was successfully used to analyze N-linked glycans released from several glycoprotein samples.

Colorimetric Sensor for Thiocyanate Based on Anti-aggregation of Gold Nanoparticles in the Presence of 2-Aminopyridine.

Based on the anti-aggregation mechanism of citrate stabilized gold nanoparticle (AuNPs), a new specific and sensitive colorimetric sensor for thiocyanate (SCN-) was developed. In this scheme, the AuNPs were aggregated in the presence of the aggregating agent 2-aminopyridine (2-AP) due to electrostatic attraction. The solution color changed from red to blue. When SCN- was present, SCN- formed a sulfur-gold bond with the AuNPs to protect the AuNPs from aggregation. Thiocyanate can be detected by the color change of the solution from blue to red. The results showed that the absorbance ratio A675/A520 was linear with the concentration of SCN- in the range of 0.4 - 1.2 µmol L-1 by UV-Vis spectroscopy. The limit of detection (LOD) of this assay was 0.37 µmol L-1. The system also had excellent selectivity and anti-interference ability. In addition, this method was successfully used for the detection of SCN- in actual water samples and achieved good results.

The Effect of p53-R249S on the Suppression of Hepatocellular Carcinoma Cells Survival Induced by Podophyllum Derivatives.

BACKGROUND: Hepatocellular Carcinoma (HCC), the second leading cause of cancer-related mortality with over half a million new cases diagnosed annually in the world, accounts for nearly 70% of cancer deaths in parts of Asia and Africa. Podophyllum, one of the important members of the lignane class of natural products derived from plants in Podophyllum peltatum L., has been shown to suppress tumor growth in various cancers. However, the effects of Podophyllum compounds on HCC and the mechanisms for its tumor-suppressive function remain unknown. METHODS: A molecular docking study was employed to the analysis of the interaction between compounds and their targeted proteins. Cell proliferation was measured by MTT assay. Western blot analysis was used to evaluate protein expression. qRT-PCR was performed to assess RNA expression. RESULTS: Molecular docking analysis was consistent with the beneficial effect of fluorine atom substituent in the 3-position of 2-aminopyridine in our previous study. Also, P-3F and D-3F displayed the most potent cytotoxicities against PLC/PRF/5 with p53-R249S and weakest inhibition of L02 (normal liver cell) growth. However, these derivatives had no effect on the suppression of HepG2 (wild-type p53) and Hep3B (p53-null) proliferation significantly. Further study showed that both compounds increase γ-H2AX expression in PLC/PRF/5 cell, along with repression of the c-Myc activation, purportedly by induction of p53 level and transcriptional activation. CONCLUSION: The results suggested that podophyllum derivatives containing fluorine atom in the 3-position of 2- aminopyridine could inhibit the growth of HCC harboring p53-R249S by restoring the activity of p53 with decreasing the level of c-Myc.