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Current Medicinal Chemistry 2024Imidazo[4,5-b]pyridines are amongst the oldest known heteroaromatic derivatives. Their structural similarity with purine basis has however aroused the curiosity of... (Review)
Review
Imidazo[4,5-b]pyridines are amongst the oldest known heteroaromatic derivatives. Their structural similarity with purine basis has however aroused the curiosity of biologists and resulted in the developments of innovative bioactive compounds. This review thus firstly describes the main synthetic ways currently used to produce imidazo[ 4,5-b]pyridine derivatives, and secondly gives examples of their potential, especially focusing on protein inhibition abilities, thus opening the way to applications as anti-cancer or antimicrobial agents.
Topics: Humans; Anti-Infective Agents; Pyridines; Structure-Activity Relationship
PubMed: 37170991
DOI: 10.2174/0929867330666230426111650 -
Bioorganic Chemistry Nov 2023Considering the fundamental role of protein kinases in the mechanism of protein phosphorylation in critical cellular processes, their dysregulation, especially in... (Review)
Review
Considering the fundamental role of protein kinases in the mechanism of protein phosphorylation in critical cellular processes, their dysregulation, especially in cancers, has underscored their therapeutic relevance. Imidazopyridines represent versatile scaffolds found in abundant bioactive compounds. Given their structural features, imidazopyridines have possessed pivotal potency to interact with different protein kinases, inspiring researchers to carry out numerous structural variations. In this comprehensive review, we encompass an extensive survey of the design and biological evaluations of imidazopyridine-based small molecules as potential agents targeting diverse kinases for anticancer applications. We describe the structural elements critical to inhibitory potency, elucidating their key structure-activity relationships (SAR) and mode of actions, where available. We classify these compounds into two groups: Serine/threonine and Tyrosine inhibitors. By highlighting the promising role of imidazopyridines in kinase inhibition, we aim to facilitate the design and development of more effective, targeted compounds for cancer treatment.
Topics: Antineoplastic Agents; Imidazoles; Phosphorylation; Pyridines; Humans
PubMed: 37683538
DOI: 10.1016/j.bioorg.2023.106831 -
Water Science and Technology : a... Apr 2024The sp. BN6-4 capable of degrading high concentrations of pyridine was isolated from the coking sludge. The removal rate of BN6-4 to 1,000 mg/L pyridine during 48 h was...
The sp. BN6-4 capable of degrading high concentrations of pyridine was isolated from the coking sludge. The removal rate of BN6-4 to 1,000 mg/L pyridine during 48 h was 97.49 ±1.59%. The primary intermediate metabolites of pyridine degradation by strain BN6-4 were identified by gas chromatography-mass spectrometry (GC-MS), including N-Ethylurea, acetamidoacetaldehyde, and N-Hydroxymethylacetamide, etc Subsequently, two different biodegradation pathways of pyridine were proposed. First, the hydroxylation of pyridine to form the intermediates pyridin-2(1H)-one and 5,6-dihydropyridine-2,5-diol, the former undergoing oxidative ring opening and the latter oxidative ring opening via N-C2 and C2-C3 ring opening to ammonia and carbon dioxide. Furthermore, the organic matter was greatly degraded by the bioremediation of real coking wastewater using BN6-4. This study enriched the microbial resource for pyridine degradation and provided new insights about the biodegradation pathway of pyridine, which is of great significance for the pyridine pollution control and coking wastewater treatment.
Topics: Pyridines; Biodegradation, Environmental; Water Pollutants, Chemical; Sewage
PubMed: 38678405
DOI: 10.2166/wst.2024.108 -
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 -
Dalton Transactions (Cambridge, England... Jul 2023Bioorganometallic complexes have attracted considerable interest and have shown promise for potential application in the treatment and diagnosis of cancer, as well as...
Bioorganometallic complexes have attracted considerable interest and have shown promise for potential application in the treatment and diagnosis of cancer, as well as bioimaging agents, some acting as theranostic agents. The series of novel ferrocene, benzimidazo[1,2-]quinoline and fluorescein derivatives with bidentate pyridyl-1,2,3-triazole and 2,2'-dipyridylamine and their tricarbonylrhenium(I) complexes was prepared and fully characterised by NMR, single-crystal X-ray diffraction, UV-Vis and fluorescence spectroscopy in biorelevant conditions. The fluorescein and benzimidazo[1,2-]quinoline ligands and their complexes with Re(I) showed interactions with ds-DNA/RNA and HSA, characterised by thermal denaturation measurements, fluorimetric and circular dichroism titrations. The binding constants revealed that addition of Re(I) increases the affinity of fluorescein but decreases the affinity of benzimidazo[1,2-]quinoline. The complexation of Re(I) had the opposite effect on fluorescein and benzimidazo[1,2-]quinoline ligands' fluorimetric sensitivity upon biomacromolecule binding, Re(I) fluorescein complex emission being strongly quenched by DNA/RNA or HSA, while emission of Re(I) benzimidazo[1,2-]quinolone complex was enhanced, particularly for HSA, making it a promising fluorescent probe. Some mono- and heterobimetallic complexes showed considerable antiproliferative activity on colon cancer cells (CT26 and HT29), with ferrocene dipyridylamine complexes exhibiting the best inhibitory activity, comparable to cisplatin. The correlation of the cytotoxicity data with the linker type between the ferrocene and the 1,2,3-triazole ring suggests that direct binding of the metallocene to the 1,2,3-triazole is favourable for antitumor activity. The Re(I) benzimidazo[1,2-]quinolone complex showed moderate antiproliferative activity, in contrast to the Re(I) fluorescein complex, which exhibited weak activity on CT26 cells and no activity on HT29 cells. The accumulation of the Re(I) benzimidazo[1,2-]quinolone complex in the lysosomes of CT26 cells indicates the site of its bioactivity, thus making this complex a potential theranostic agent.
Topics: Humans; Metallocenes; Ligands; Chelating Agents; DNA; Quinolones; Pyridines; Triazoles; RNA; Fluoresceins; Coordination Complexes; Antineoplastic Agents
PubMed: 37366535
DOI: 10.1039/d3dt01070h -
Sleep Nov 2023
Topics: Humans; Zolpidem; Sleep Initiation and Maintenance Disorders; Pyridines; Hypnotics and Sedatives; Behavior Therapy; Double-Blind Method
PubMed: 37691423
DOI: 10.1093/sleep/zsad240 -
Journal of Natural Products Oct 2023Eleven densely functionalized new dihydro-β-agarofuran sesquiterpenoid derivatives, named maytenoids A-K (-), as well as one known analog, were isolated and...
Eleven densely functionalized new dihydro-β-agarofuran sesquiterpenoid derivatives, named maytenoids A-K (-), as well as one known analog, were isolated and characterized from . Their structures were assigned based on analysis of spectroscopic data and X-ray crystallography. Compounds - are macrocyclic sesquiterpene pyridine alkaloids generated by the respective acylation of the hydroxy groups at C-3 and C-13 of dihydro-β-agarofuran sesquiterpenoids via diverse pyridine dicarboxylic acids. Compounds , , -, and exhibited significant inhibitory effects on NO production at 10 μM in lipopolysaccharide (LPS)-stimulated BV2 cells.
Topics: Maytenus; Molecular Structure; Alkaloids; Sesquiterpenes; Pyridines
PubMed: 37728995
DOI: 10.1021/acs.jnatprod.3c00504 -
European Journal of Medicinal Chemistry Oct 2023Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key regulator to control downstream NF-κB and MAPK signals in the innate immune response and has been proposed...
Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key regulator to control downstream NF-κB and MAPK signals in the innate immune response and has been proposed as a therapeutic target for the treatment of inflammatory and autoimmune diseases. Herein, a series of IRAK4 inhibitors based on a dihydrofuro[2,3-b]pyridine scaffold was developed. Structural modifications of the screening hit 16 (IC = 243 nM) led to IRAK4 inhibitors with improved potency but high clearance (Cl) and poor oral bioavailability, as exemplified by compound 21 (IC = 6.2 nM, Cl = 43 ml/min/kg, F = 1.6%, LLE = 5.4). Structure modification aimed at improving LLE and reducing clearance identified compound 38. Compound 38 showed significantly improved clearance while maintained excellent biochemical potency against IRAK4 (IC = 7.3 nM, Cl = 12 ml/min/kg, F = 21%, LLE = 6.0). Importantly, compound 38 had favorable in vitro safety and ADME profiles. Furthermore, compound 38 reduced the in vitro production of pro-inflammatory cytokines in both mouse iBMDMs and human PBMCs and was orally efficacious in the inhibition of serum TNF-α secretion in LPS-induced mouse model. These findings suggested that compound 38 has development potential as an IRAK4 inhibitor for the treatment of inflammatory and autoimmune disorders.
Topics: Humans; Animals; Mice; Signal Transduction; Interleukin-1 Receptor-Associated Kinases; NF-kappa B; Cytokines; Pyridines
PubMed: 37413880
DOI: 10.1016/j.ejmech.2023.115616 -
Luminescence : the Journal of... Nov 2023The spatial arrangement of molecules plays a crucial role in determining the macroscopic properties of functional materials. Coordinated polymers (CPs) formed by...
The spatial arrangement of molecules plays a crucial role in determining the macroscopic properties of functional materials. Coordinated polymers (CPs) formed by self-assembly of organic isomeric ligands and metals offer unique performance characteristics. In this study, we present the investigation of a one-dimensional CP, named CIT-E, composed of tetraphenylethene pyridine derivative (TPE-2by-2-E) ligands and copper iodide. The resulting CP exhibits a one-dimensional bead chain structure with exceptional thermal and chemical stability. By leveraging the competitive absorption between CIT-E and the explosive analog 2,4-dinitroaniline, we achieve detection of the explosive through changes in the absorption intensity of the excitation light source and subsequent fluorescence response. The CP demonstrates high selectivity and anti-interference ability in detecting 2,4-dinitroaniline in aqueous solution, with a detection linear range of 0.1 to 300 μM and a detection limit of 0.05 μM, surpassing the national third-level emission standard. These findings highlight the potential of CP CIT-E as a promising material for the detection of explosive nitroaromatic compounds.
Topics: Explosive Agents; Polymers; Fluorescence; Copper; Iodides; Pyridines
PubMed: 37559555
DOI: 10.1002/bio.4576 -
Journal of Clinical Sleep Medicine :... Jan 2024To evaluate the respiratory safety of lemborexant among adults and older adults with moderate to severe obstructive sleep apnea (OSA). (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVES
To evaluate the respiratory safety of lemborexant among adults and older adults with moderate to severe obstructive sleep apnea (OSA).
METHODS
E2006-A001-113 (Study 113; NCT04647383) was a double-blind, two-period crossover, placebo-controlled study in adults (ages ≥ 45 to ≤ 90 years, n = 33) with moderate (apnea-hypopnea index [AHI] score ≥ 15 to < 30 events/h, n = 13) or severe (AHI ≥ 30 events/h, n = 20) OSA. Participants were randomized to lemborexant 10 mg (LEM10) or placebo (PBO) for two treatment periods of 8 nights with a ≥ 14-day washout period. AHI and peripheral oxygen saturation were evaluated after treatment on Day 1 (after a single dose) and Day 8 (after multiple doses).
RESULTS
No significant differences in AHI were observed after single and multiple doses of LEM10 compared with PBO in participants with moderate to severe OSA (least-squares mean: single-dose LEM10, 41.7; PBO, 44.8; multiple-dose LEM10, 44.9; PBO, 45.7). In addition, there were no significant differences between treatments in peripheral oxygen saturation (least-squares mean: single-dose LEM10, 93.0; PBO, 93.1; multiple-dose LEM10, 93.1; PBO, 93.4). Further, there were no significant differences between treatments in percentage of total sleep time with peripheral oxygen saturation < 90%, < 85%, or < 80%. No significant differences were observed between treatments when AHI and peripheral oxygen saturation outcomes were analyzed by OSA severity. Altogether, 6/33 (18.2%) participants receiving LEM10, vs 3/33 (9.1%) PBO, reported treatment-emergent adverse events, mostly mild in severity.
CONCLUSIONS
LEM10 demonstrated respiratory safety and was well tolerated with single-dose and multiple-dose administration in participants with moderate to severe OSA. This suggests that LEM may be a treatment option for patients with OSA and comorbid insomnia.
CLINICAL TRIAL REGISTRATION
Registry: ClinicalTrials.gov; Name: A Study to Evaluate the Respiratory Safety of Lemborexant in Adult and Elderly Participants With Moderate to Severe Obstructive Sleep Apnea and in Adult and Elderly Participants With Moderate to Severe Chronic Obstructive Pulmonary Disease; URL: https://clinicaltrials.gov/ct2/show/NCT04647383; Identifier: NCT04647383.
CITATION
Cheng JY, Lorch D, Lowe AD, et al. A randomized, double-blind, placebo-controlled, crossover study of respiratory safety of lemborexant in moderate to severe obstructive sleep apnea. . 2024;20(1):57-65.
Topics: Humans; Aged; Cross-Over Studies; Pyridines; Pyrimidines; Sleep Apnea, Obstructive; Double-Blind Method
PubMed: 37677076
DOI: 10.5664/jcsm.10788