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Molecular Diversity Apr 2023Two new categories of fused pyridines include 2H-thiazolo[3,2-a]pyridine-6-carbohydrazides and 2H-oxazolo[3,2-a]pyridine-6-carbohydrazides have been successfully...
Two new categories of fused pyridines include 2H-thiazolo[3,2-a]pyridine-6-carbohydrazides and 2H-oxazolo[3,2-a]pyridine-6-carbohydrazides have been successfully synthesized via five-component cascade reactions using 9-fluorenone, cyanoacetohydrazide, 1,1-bis(methylthio)-2-nitroethene, aromatic aldehydes and cysteamine hydrochloride or ethanol amine as starting materials. This new approach involves a subsequence of key steps: N,S-acetal or N,O-acetal formation, Knoevenagel condensation, Michael addition, tautomerization and N-cyclization. It also has some advantages, such as convenience of operation, tolerance of a wide diversity of functional groups, use of green solvent and ease of purification by washing the crude products with ethanol.
Topics: Molecular Structure; Acetals; Pyridines; Ethanol
PubMed: 35587848
DOI: 10.1007/s11030-022-10446-0 -
European Journal of Medicinal Chemistry Nov 2019This article provides an overview of compounds based on imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine scaffolds,... (Review)
Review
This article provides an overview of compounds based on imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine scaffolds, which act as potent ligands of diverse molecular targets localized in the central nervous system. A literature survey revealed that various imidazopyridines can be powerful modulators of several diseases associated with CNS dysfunction including Alzheimer's disease, Parkinson's disease, schizophrenia, depression or sleeping disorders. A description of target enzymes (e.g., β-secretase, γ-secretase, fatty acid amide hydrolase - FAAH, leucine-rich repeat kinase 2 - LRRK2) and selected receptors (e.g., GABA-A, histamine H, serotonin 5-HT, 5-HT, 5-HT, dopamine D, adenosine A, orexin), modes of action of imidazopyridine-based ligands and their therapeutic importance is discussed.
Topics: Animals; Clinical Trials as Topic; Drug Design; Humans; Imidazoles; Ligands; Mental Disorders; Molecular Targeted Therapy; Neurodegenerative Diseases; Pyridines
PubMed: 31404862
DOI: 10.1016/j.ejmech.2019.111569 -
Molecules (Basel, Switzerland) Jun 2021New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from...
New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine- functionalized derivatives. The derived pyrazolpyridine--glycosides were synthesized via heterocyclization of the -thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative and the tricyclic pyrido[3',2':4,5]furo[3,2-d]pyrimidine were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone , 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1-pyrazolo[3,4-b]pyridin-3-amine (), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate () are among the most active inhibitors with IC values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC ranges of 31.3-49.0, 19.3-55.5, 22.7-44.8, and 36.8-70.7 μM, respectively compared to doxorubicin (IC 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase 2; Dose-Response Relationship, Drug; Doxorubicin; Drug Design; Drug Screening Assays, Antitumor; Humans; Imidazoles; Inhibitory Concentration 50; Molecular Docking Simulation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Quantitative Structure-Activity Relationship
PubMed: 34206976
DOI: 10.3390/molecules26133923 -
European Journal of Medicinal Chemistry Nov 2023Multidrug-resistant Escherichia coli is a continuously growing worldwide public health problem, in which the well-known AcrAB-TolC tripartite RND efflux pump is a...
Multidrug-resistant Escherichia coli is a continuously growing worldwide public health problem, in which the well-known AcrAB-TolC tripartite RND efflux pump is a critical driver. We have previously described pyridylpiperazines as a novel class of allosteric inhibitors of E. coli AcrB which bind to a unique site in the protein transmembrane domain, allowing for the potentiation of antibiotic activity. Here, we show a rational optimization of pyridylpiperazines by modifying three specific derivatization points of the pyridine core to improve the potency and the pharmacokinetic properties of this chemical series. In particular, this work found that the introduction of a primary amine to the pyridine through ester (29, BDM91270) or oxadiazole (44, BDM91514) based linkers allowed for analogues with improved antibiotic boosting potency through AcrB inhibition. In vitro studies, using genetically engineered mutants, showed that this improvement in potency is mediated through novel interactions with distal acidic residues of the AcrB binding pocket. Of the two leads, compound 44 was found to have favorable physico-chemical properties and suitable plasma and microsomal stability. Together, this work expands the current structure-activity relationship data on pyridylpiperazine efflux pump inhibitors, and provides a promising step towards future in vivo proof of concept of pyridylpiperazines as antibiotic potentiators.
Topics: Escherichia coli; Escherichia coli Proteins; Anti-Bacterial Agents; Pyridines; Multidrug Resistance-Associated Proteins; Carrier Proteins
PubMed: 37459793
DOI: 10.1016/j.ejmech.2023.115630 -
Natural Product Research Jun 2024In the present study, three series of 35 pyridine-based stilbenes include 10 new compounds prepared by Horner-Wadsworth-Emmons (HWE) reaction were assayed for cytotoxic...
In the present study, three series of 35 pyridine-based stilbenes include 10 new compounds prepared by Horner-Wadsworth-Emmons (HWE) reaction were assayed for cytotoxic activities toward two tumoral cell lines (K562 and MDA-MB-231) and one non-tumoral cell line (L-02). The bioassay results indicated that hybrid stilbenes formed at the C-3 position of pyridine displayed stronger antiproliferative activities against K562 cells and C-4 pyridine-based stilbenes showed broad-spectrum cytotoxic effects. Among them, C-3 pyridine-based stilbene bearing 2,6-dimethoxy possessed extremely potent antiproliferative activity with IC values 1.46 µM against K562 cells, along with excellent selectivity towards normal L-02 cells. In summary, the present study contributes to the development of natural stilbene-based derivatives as antitumor agents and may serve as a promising lead for the treatment of chronic myeloid leukemia (CML) worthy further investigation.
Topics: Stilbenes; Humans; Pyridines; Antineoplastic Agents; K562 Cells; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Molecular Structure; Structure-Activity Relationship
PubMed: 37384584
DOI: 10.1080/14786419.2023.2227991 -
Molecules (Basel, Switzerland) Nov 2022Antimicrobial resistance is on the rise, and there aren't enough new treatments to combat it. This might send the modern world back to the pre-antibiotic age. The...
Antimicrobial resistance is on the rise, and there aren't enough new treatments to combat it. This might send the modern world back to the pre-antibiotic age. The molecular hybrids of pyrazolo[3,4-]pyridine and triazole have been designed, synthesized, and analyzed for their drug-like molecule nature and in vitro analyses for their inhibition potentials against and . The compounds and have been identified as the high potential molecules in this series based on in vitro experiments. Compound has zone of inhibition values of 15 ± 0.82 mm and 14 ± 0.7 mm, whilst compound has zone of inhibition values of 18 ± 0.95 mm and 16 ± 0.82 mm against and , respectively. MIC and MIB values for compounds and against and are 0.25 and 0.5, respectively.
Topics: Triazoles; Microbial Sensitivity Tests; Staphylococcus aureus; Anti-Bacterial Agents; Pyridines; Klebsiella pneumoniae; Structure-Activity Relationship
PubMed: 36364469
DOI: 10.3390/molecules27217647 -
Journal of the American Chemical Society Aug 2022Herein, we report a method for C3-selective C-H tri- and difluoromethylthiolation of pyridines. The method relies on borane-catalyzed pyridine hydroboration for...
Herein, we report a method for C3-selective C-H tri- and difluoromethylthiolation of pyridines. The method relies on borane-catalyzed pyridine hydroboration for generation of nucleophilic dihydropyridines; these intermediates react with trifluoromethylthio and difluoromethylthio electrophiles to form functionalized dihydropyridines, which then undergo oxidative aromatization. The method can be used for late-stage functionalization of pyridine drugs for the generation of new drug candidates.
Topics: Dihydropyridines; Molecular Structure; Pyridines
PubMed: 35913823
DOI: 10.1021/jacs.2c06776 -
Journal of the American Chemical Society Nov 2019The catalytic, enantioselective -oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high...
The catalytic, enantioselective -oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine -oxides further document the utility of this approach. Demonstration of the asymmetric -oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.
Topics: Aspartic Acid; Catalysis; Heterocyclic Compounds; Hydrogen Bonding; Peptides; Pyridines; Stereoisomerism
PubMed: 31656070
DOI: 10.1021/jacs.9b10414 -
Nature Communications Jan 2021Although various methods have been developed for sequencing cytosine modifications, it is still challenging for specific and quantitative sequencing of individual...
Although various methods have been developed for sequencing cytosine modifications, it is still challenging for specific and quantitative sequencing of individual modification at base-resolution. For example, to obtain both true 5-methylcytosine (5mC) and true 5-hydroxymethylcytosine (5hmC) information, the two major epigenetic modifications, it usually requires subtraction of two methods, which increases noise and requires high sequencing depth. Recently, we developed TET-assisted pyridine borane sequencing (TAPS) for bisulfite-free direct sequencing of 5mC and 5hmC. Here we demonstrate that two sister methods, TAPSβ and chemical-assisted pyridine borane sequencing (CAPS), can be effectively used for subtraction-free and specific whole-genome sequencing of 5mC and 5hmC, respectively. We also demonstrate pyridine borane sequencing (PS) for whole-genome profiling of 5-formylcytosine and 5-carboxylcytosine, the further oxidized derivatives of 5mC and 5hmC. This work completes the set of versatile borane reduction chemistry-based methods as a comprehensive toolkit for direct and quantitative sequencing of all four cytosine epigenetic modifications.
Topics: 5-Methylcytosine; Animals; Base Sequence; Mice; Mouse Embryonic Stem Cells; Oxidation-Reduction; Pyridines; Sequence Analysis, DNA; Sulfites
PubMed: 33504799
DOI: 10.1038/s41467-021-20920-2 -
Chembiochem : a European Journal of... Aug 2020Five copper complexes supported by terpyridine ligands were prepared and characterized, viz. [Cu Cl (naphtpy) ][CuCl ] (1), [Cu Cl (naphtpy) ](ClO ) (2), [CuCl...
Five copper complexes supported by terpyridine ligands were prepared and characterized, viz. [Cu Cl (naphtpy) ][CuCl ] (1), [Cu Cl (naphtpy) ](ClO ) (2), [CuCl (naphtpy)] (MeOH) (H O) (3), [CuCl (Cltpy)] (4) and [Cu(Cltpy) ](ClO ) (5); (where naphtpy stands for 4'-((naphthalen-2-yl)methoxy)-2,2':6',2''-terpyridine and Cltpy for 4'-chloro-2,2':6',2''-terpyridine). Their ability to interact with DNA was investigated, and their cytotoxic behaviour was examined with three cells lines, namely human ovarian carcinoma cells (A2780), their derived cisplatin-resistant line (A2780cis), and human cervix adenocarcinoma cells (HeLa). All compounds show good cytotoxic properties (especially after 72 h of incubation). Remarkably, two compounds, 4 and 5, are still almost inactive after 24 h (particularly 4), but are highly active after 72 h, with IC values in the low-micromolar to sub-micromolar range. Compounds 1 and 2 induce necrosis, whereas late apoptosis is observed with 3-5, 4 exhibiting a behaviour close to that of cisplatin.
Topics: Antineoplastic Agents; Cell Line, Tumor; Coordination Complexes; Copper; DNA; Humans; Kinetics; Models, Molecular; Nucleic Acid Conformation; Pyridines
PubMed: 32212203
DOI: 10.1002/cbic.202000154