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Medicinal Chemistry (Shariqah (United... 2023Chalcones are precursors of flavonoids and exhibit a broad spectrum of pharmacological activity.
BACKGROUND
Chalcones are precursors of flavonoids and exhibit a broad spectrum of pharmacological activity.
OBJECTIVE
As anti-inflammatory agents, two series of chalcone derivatives and chalcone-based oximes were synthesized and characterized. To integrate the tetramethylpyrazine moiety into these novel molecules, the multifunctional natural chemical ligustrazine was employed.
METHODS
A variety of newly synthesized ligustrazine-based chalcones were utilized as precursors for the synthesis of new oximes and their inhibitory activity against COX-1, COX-2, and LOX-5 enzymes were compared.
RESULTS
The conversion of ketones to their oxime derivatives increased the effectiveness of COX-1 and COX-2 inhibition. Due to the substituted ether groups, oxime derivative 5d had the lowest IC values of 0.027 ± 0.004 μM and 0.150 ± 0.027 μM for COX-1 and COX-2 isoenzymes, respectively. Notably, the oxime derivative's highest effectiveness is conferred by the presence of methoxymethoxy or hydroxy groups at the C-3 and C-4 positions on the phenyl ring. The 6b derivative with a long alkyl chain ether group was shown to be the most powerful 5-LOX inhibitor. All compounds were also assessed for their ability to inhibit nitric oxide generation and LPS-induced IL-6, IL-1β, and TNF-α production in RAW 264.7 macrophages. Finally, in order to determine the structural effects responsible for the binding mechanism of compounds, they were docked into the binding sites of COX-1, COX-2, and 5-LOX, which revealed an inhibitory mechanism of action and demonstrated the relevance of various types of interactions.
CONCLUSION
The findings showed that these novel compounds had a significant impact on antiinflammatory actions.
Topics: Chalcone; Chalcones; Cyclooxygenase 2; Structure-Activity Relationship; Anti-Inflammatory Agents; Oximes
PubMed: 36635904
DOI: 10.2174/1573406419666230112110306 -
Journal of Enzyme Inhibition and... Dec 2020Cyclic imides containing 3-benzenesulfonamide, oxime, and β-phenylalanine derivatives were synthesised and evaluated to elucidate their anti-inflammatory and...
Synthesis, anti-inflammatory, cytotoxic, and COX-1/2 inhibitory activities of cyclic imides bearing 3-benzenesulfonamide, oxime, and β-phenylalanine scaffolds: a molecular docking study.
Cyclic imides containing 3-benzenesulfonamide, oxime, and β-phenylalanine derivatives were synthesised and evaluated to elucidate their anti-inflammatory and ulcerogenic activity and cytotoxic effects. Most active anti-inflammatory agents were subjected to COX-1/2 inhibition assay. 3-Benzenesulfonamides (, and ), oximes (), and β-phenylalanine derivative () showed potential anti-inflammatory activities with 71.2-82.9% oedema inhibition relative to celecoxib and diclofenac (85.6 and 83.4%, respectively). Most active cyclic imides , , , , and possessed ED of 35.4-45.3 mg kg relative to that of celecoxib (34.1 mg kg). For the cytotoxic evaluation, the selected derivatives and exhibited weak positive cytotoxic effects (PCE = 2/59-5/59) at 10 μM compared to the standard drug, imatinib (PCE = 20/59). Cyclic imides bearing 3-benzenesulfonamide (, and ), acetophenone oxime (, , and ) exhibited high selectivity against COX-2 with SI > 55.6-333.3 relative to that for celecoxib [SI > 387.6]. β-Phenylalanine derivatives and were non-selective towards COX-1/2 isozymes as indicated by their SI of 0.46-0.68.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Edema; Humans; Imides; Molecular Docking Simulation; Molecular Structure; Oximes; Phenylalanine; Rats; Structure-Activity Relationship; Sulfonamides; Benzenesulfonamides
PubMed: 32013633
DOI: 10.1080/14756366.2020.1722120 -
Inorganic Chemistry Apr 2023A novel material with dual activity toward organophosphate (OP) poisoning, based on Zr-MOF-808 and neutral oxime RS69N, has been prepared. The hybrid material has a...
A novel material with dual activity toward organophosphate (OP) poisoning, based on Zr-MOF-808 and neutral oxime RS69N, has been prepared. The hybrid material has a significant drug payload (5.2 ± 0.9 oxime to MOF-808 molar ratio) and shows a sustained oxime release in simulated physiological media, leading to the successful reactivation of OP-inhibited acetylcholinesterase. At the same time, the hybrid system presents an efficient and moderately fast removal rate of a toxic organophosphorus model compound (diisopropylfluorophosphate) from simulated physiological media ( = 183 min; 95% removal rate after 24 h).
Topics: Humans; Oximes; Antidotes; Organophosphate Poisoning; Cholinesterase Reactivators; Metal-Organic Frameworks; Zirconium; Acetylcholinesterase; Cholinesterase Inhibitors; Organophosphorus Compounds
PubMed: 36939843
DOI: 10.1021/acs.inorgchem.3c00121 -
Steroids Jun 2022Using cholesterol and diosgenin as starting materials, we have designed a straightforward methodology to prepare in a reduced number of steps a novel series of steroidal...
Using cholesterol and diosgenin as starting materials, we have designed a straightforward methodology to prepare in a reduced number of steps a novel series of steroidal oximes and their aza-homolactam analogs with four types of side chains: cholestane, spirostane, 22-oxocholestane and 22,26-epoxycholestene. The products were evaluated for their cytotoxic activity against the MCF-7 breast cancer cell line. Moreover, the selectivity of the most active compounds was determined against peripheral blood lymphocytes. Compounds 5, 8 and 13 were found to be the most active derivatives, exhibiting IC values in the low micromolar range (7.9-9.5 µM) and excellent selectivities (IC > 100 µM) against the non-tumor cell line.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cholesterol; Diosgenin; Drug Screening Assays, Antitumor; Homosteroids; Molecular Structure; Oximes; Steroids; Structure-Activity Relationship
PubMed: 35307325
DOI: 10.1016/j.steroids.2022.109012 -
The Journal of Organic Chemistry Jun 2023A 2'-deoxycytidin-4-yl radical (dC·), a strong oxidant that also abstracts hydrogen atoms from carbon-hydrogen bonds, is produced in a variety of DNA damaging...
A 2'-deoxycytidin-4-yl radical (dC·), a strong oxidant that also abstracts hydrogen atoms from carbon-hydrogen bonds, is produced in a variety of DNA damaging processes. We describe here the independent generation of dC· from oxime esters under UV-irradiation or single electron transfer conditions. Support for this σ-type iminyl radical generation is provided by product studies carried out under aerobic and anaerobic conditions, as well as electron spin resonance (ESR) characterization of dC· in a homogeneous glassy solution at low temperature. Density functional theory (DFT) calculations also support fragmentation of the corresponding radical anions of oxime esters and to dC· and subsequent hydrogen atom abstraction from organic solvents. The corresponding 2'-deoxynucleotide triphosphate (dNTP) of isopropyl oxime ester () is incorporated opposite 2'-deoxyadenosine and 2'-deoxyguanosine by a DNA polymerase with approximately equal efficiency. Photolysis experiments of DNA containing support dC· generation and indicate that the radical produces tandem lesions when flanked on the 5'-side by 5'-d(GGT). These experiments suggest that oxime esters are reliable sources of nitrogen radicals in nucleic acids that will be useful mechanistic tools and possibly radiosensitizing agents when incorporated in DNA.
Topics: Free Radicals; Oximes; Esters; Electrons; DNA; Hydrogen
PubMed: 37220149
DOI: 10.1021/acs.joc.3c00646 -
Chemical Communications (Cambridge,... Jan 2020We report an elastase-responsive, H2S-releasing hydrogel prepared by covalently crosslinking a mixture of carboxymethylcellulose and poly(ethylene glycol) with an...
We report an elastase-responsive, H2S-releasing hydrogel prepared by covalently crosslinking a mixture of carboxymethylcellulose and poly(ethylene glycol) with an elastase-degradable peptide functionalized with an H2S-releasing S-aroylthiooxime (SATO) unit. Addition of elastase triggered a gel-to-sol transition, which exposed SATOs, leading to more and longer H2S release compared to untriggered gels.
Topics: Animals; Carboxymethylcellulose Sodium; Cell Line; Doxorubicin; Humans; Hydrogels; Hydrogen Sulfide; Leukocyte Elastase; Oxidative Stress; Oximes; Polyethylene Glycols; Protective Agents; Rats
PubMed: 31894779
DOI: 10.1039/c9cc08752d -
Organic Letters Mar 2022The preparation of 2,2,2-trifluoroacetaldehyde -(aryl)oxime, a previously inaccessible precursor of trifluoroacetonitrile, via reaction of hydroxylamine and...
The preparation of 2,2,2-trifluoroacetaldehyde -(aryl)oxime, a previously inaccessible precursor of trifluoroacetonitrile, via reaction of hydroxylamine and trifluoroacetaldehyde hydrate is reported. This precursor released CFCN in quantitative yield under mildly basic conditions. The precursor was successfully used in the synthesis of trifluoromethylated oxadiazoles. The facile, cost-effective, scalable, and recyclable procedure makes these trifluoroacetonitrile precursors generally applicable.
Topics: Acetaldehyde; Oxadiazoles; Oximes
PubMed: 35266394
DOI: 10.1021/acs.orglett.2c00637 -
PloS One 2023The ability of the cyclodextrin-oxime construct 6-OxP-CD to bind and degrade the nerve agents Cyclosarin (GF), Soman (GD) and S-[2-[Di(propan-2-yl)amino]ethyl] O-ethyl...
Evaluation of 6-OxP-CD, an Oxime-based cyclodextrin as a viable medical countermeasure against nerve agent poisoning: Experimental and molecular dynamic simulation studies on its inclusion complexes with cyclosarin, soman and VX.
The ability of the cyclodextrin-oxime construct 6-OxP-CD to bind and degrade the nerve agents Cyclosarin (GF), Soman (GD) and S-[2-[Di(propan-2-yl)amino]ethyl] O-ethyl methylphosphonothioate (VX) has been studied using 31P-nuclear magnetic resonance (NMR) under physiological conditions. While 6-OxP-CD was found to degrade GF instantaneously under these conditions, it was found to form an inclusion complex with GD and significantly improve its degradation (t1/2 ~ 2 hrs) relative over background (t1/2 ~ 22 hrs). Consequently, effective formation of the 6-OxP-CD:GD inclusion complex results in the immediate neutralization of GD and thus preventing it from inhibiting its biological target. In contrast, NMR experiments did not find evidence for an inclusion complex between 6-OxP-CD and VX, and the agent's degradation profile was identical to that of background degradation (t1/2 ~ 24 hrs). As a complement to this experimental work, molecular dynamics (MD) simulations coupled with Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) calculations have been applied to the study of inclusion complexes between 6-OxP-CD and the three nerve agents. These studies provide data that informs the understanding of the different degradative interactions exhibited by 6-OxP-CD with each nerve agent as it is introduced in the CD cavity in two different orientations (up and down). For its complex with GF, it was found that the oxime in 6-OxP-CD lies in very close proximity (PGF⋯OOxime ~ 4-5 Å) to the phosphorus center of GF in the 'downGF' orientation for most of the simulation accurately describing the ability of 6-OxP-CD to degrade this nerve agent rapidly and efficiently. Further computational studies involving the center of masses (COMs) for both components (GF and 6-OxP-CD) also provided some insight on the nature of this inclusion complex. Distances between the COMs (ΔCOM) lie closer in space in the 'downGF' orientation than in the 'upGF' orientation; a correlation that seems to hold true not only for GF but also for its congener, GD. In the case of GD, calculations for the 'downGD' orientation showed that the oxime functional group in 6-OxP-CD although lying in close proximity (PGD⋯OOxime ~ 4-5 Å) to the phosphorus center of the nerve agent for most of the simulation, adopts another stable conformation that increase this distance to ~ 12-14 Å, thus explaining the ability of 6-OxP-CD to bind and degrade GD but with less efficiency as observed experimentally (t1/2 ~ 4 hr. vs. immediate). Lastly, studies on the VX:6-OxP-CD system demonstrated that VX does not form a stable inclusion complex with the oxime-bearing cyclodextrin and as such does not interact in a way that is conducive to an accelerated degradation scenario. Collectively, these studies serve as a basic platform from which the development of new cyclodextrin scaffolds based on 6-OxP-CD can be designed in the development of medical countermeasures against these highly toxic chemical warfare agents.
Topics: Soman; Nerve Agents; Oximes; Molecular Dynamics Simulation; Cyclodextrins; Medical Countermeasures; Organophosphorus Compounds; Chemical Warfare Agents; Phosphorus
PubMed: 36996021
DOI: 10.1371/journal.pone.0283181 -
Bioorganic Chemistry Jul 2020A new series of novel nonquaternary conjugates and non-oxime reactivators for reactivation of both nerve agents and pesticides inhibited hAChE were described in this...
A new series of novel nonquaternary conjugates and non-oxime reactivators for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. Conjugates with piperazine linked to the substituted salicylaldoxime emerged as efficient reactivators for VX inhibited hAChE. The in vitro reactivation experiment showed that some of them were equal or more efficient reactivators for pesticides inhibited hAChE than obidoxime. It was also found that some non-oxime derivatives of Mannich phenols displayed obvious reactivation potency for VX, sarin and pesticides inhibited hAChE even in very low concentration. It has been proved that introduction of peripheral site ligands with widespread aromatic system and amide substitutions could increase binding affinity for inhibited hAChE in most cases, which contribute to the reactivation efficiency.
Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; Drug Design; Humans; Kinetics; Molecular Docking Simulation; Nerve Agents; Organophosphates; Oximes; Pesticides; Piperazine
PubMed: 32388435
DOI: 10.1016/j.bioorg.2020.103902 -
Future Medicinal Chemistry May 2021Nonapoptotic types of regulated cell death have attracted widespread interest since the discovery that certain forms of cell necrosis can be regulated. In particular,... (Review)
Review
Nonapoptotic types of regulated cell death have attracted widespread interest since the discovery that certain forms of cell necrosis can be regulated. In particular, research into cell necroptosis has made significant progress in connection with kidney, inflammatory, degenerative and neoplastic diseases. Inhibitors targeting the critical necroptosis-associated proteins RIPK1/3 and MLKL have been in development for more than a decade. Herein the authors compile a list of the known small-molecule inhibitors of these enzymes and representative structures of compounds co-crystallized with these proteins and put forward some thoughts regarding their future development.
Topics: Animals; Apoptosis; Humans; Imidazoles; Necroptosis; Necrosis; Oximes; Protein Binding; Protein Conformation; Protein Kinase Inhibitors; Protein Kinases; Pyrimidines; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 33845591
DOI: 10.4155/fmc-2020-0386