-
Bioorganic Chemistry Jul 2024Thirty-five trifluoromethyl hydrazones and seventeen trifluoromethyl oxime esters were designed and synthesized via molecular hybridization. All the target compounds...
Thirty-five trifluoromethyl hydrazones and seventeen trifluoromethyl oxime esters were designed and synthesized via molecular hybridization. All the target compounds were initially screened for in vitro anti-inflammatory activity by assessing their inhibitory effect on NO release in LPS-stimulated RAW264.7 cells, and the optimal compound was finally identified as 2-(3-Methoxyphenyl)-N'-((6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-6,9,12,15-tetraen-2-ylidene)acetohydrazide (F26, IC = 4.55 ± 0.92 μM) with no cytotoxicity. Moreover, F26 potently reduced the production of PGE in LPS-stimulated RAW264.7 cells compared to indomethacin. The interaction of F26 with COX-2 and cPLA was directly verified by the CETSA technique. F26 was found to modulate the phosphorylation levels of p38 MAPK and NF-κB p65, as well as the protein expression of IκB, cPLA, COX-2, and iNOS in LPS-stimulated rat peritoneal macrophages. Additionally, F26 was observed to prevent the nuclear translocation of NF-κB p65 in LPS-stimulated rat peritoneal macrophages by immunofluorescence localization. Therefore, the aforementioned in vitro experiments demonstrated that F26 blocked the p38 MAPK and NF-κB pathways by binding to COX-2 and cPLA. In the adjuvant-induced arthritis model, F26 demonstrated a significant effect in preventing arthritis symptoms and inflammatory status in rats, exerting an immunomodulatory role by regulating the homeostasis between Th17 and Treg through inhibition of the p38 MAPK/cPLA/COX-2/PGE and NF-κB pathways. Encouragingly, F26 caused less acute ulcerogenicity in rats at a dose of 50 mg/kg compared to indomethacin. Overall, F26 is a promising candidate worthy of further investigation for treating inflammation and associated pain with lesser gastrointestinal irritation, as well as other symptoms in which cPLA and COX-2 are implicated in the pathophysiology.
Topics: Animals; Mice; Cyclooxygenase 2; Arthritis, Rheumatoid; RAW 264.7 Cells; Cyclooxygenase 2 Inhibitors; Rats; Structure-Activity Relationship; Molecular Structure; Inflammation; Male; Dose-Response Relationship, Drug; Ketones; Lipopolysaccharides; Anti-Inflammatory Agents, Non-Steroidal; Phospholipases A2; Administration, Oral; Rats, Sprague-Dawley
PubMed: 38761708
DOI: 10.1016/j.bioorg.2024.107453 -
Journal of Colloid and Interface Science Sep 2024Macrophages can kill bacteria and viruses by releasing free radicals, which provides a possible approach to construct antifouling coatings with dynamic surfaces that...
Macrophages can kill bacteria and viruses by releasing free radicals, which provides a possible approach to construct antifouling coatings with dynamic surfaces that release free radicals if the breaking of dynamic covalent bonds is precisely regulated. Herein, inspired by the defensive behavior of macrophages of releasing free radicals to kill bacteria and viruses, a marine antifouling coating composed of polyurethane incorporating dimethylglyoxime (PU-DMG) is prepared by precise regulation of dynamic oxime-urethane covalent bonds. The obtained alkyl radical (R·) derived from the cleavage of the oxime-urethane bonds manages to effectively suppress the attachment of marine biofouling. Moreover, the intrinsic dynamic surface makes it difficult for biofouling to adhere and ultimately achieves sustainable antifouling property. Notably, the PU-DMG coating not only presents efficient antibacterial and antialgae properties, but also prevents macroorganisms from settling in the sea for up to 4 months. This provides a pioneer broad-spectrum strategy to explore the marine antifouling coatings.
Topics: Biofouling; Surface Properties; Macrophages; Animals; Anti-Bacterial Agents; Polyurethanes; Mice; Oximes; RAW 264.7 Cells; Particle Size; Microbial Sensitivity Tests; Molecular Structure
PubMed: 38761575
DOI: 10.1016/j.jcis.2024.05.089 -
Journal of Pharmaceutical and... Aug 2024In this study, the first nanomaterial-supported molecularly imprinted polymer (MIP)-based electrochemical approach was proposed to achieve the successful detection of... (Review)
Review
Nanomaterial-assisted molecularly imprinted polymer strategies for highly sensitive and selective determination of cefdinir and its validation using computational approach.
In this study, the first nanomaterial-supported molecularly imprinted polymer (MIP)-based electrochemical approach was proposed to achieve the successful detection of cefdinir (CFD). Here, p-amino benzoic acid (p-ABA) was used as the monomer and the photopolymerization method was chosen to form MIP on a glassy carbon electrode (GCE). ZnO nanoparticles (ZnO NPs) were added to the MIP sensor to increase sensitivity and create high porosity. Through the use of cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), characterization investigations confirmed the alterations at each stage of the MIP production process. Electrochemical (cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS)) and scanning electron microscopy (SEM) methods were used for study the characterization studies of the MIP-based nanocomposite sensor. The measurement of MIP parameters, such as the addition of nanoparticles, the removal procedure, the rebinding period, the monomer ratio, etc., was done using the differential pulse voltammetry (DPV). The findings showed that when ZnO NPs were added, the signal was three times higher than when MIPs were used alone. Under the optimized conditions, CFD/4-ABA@ZnONPs/MIP/GCE showed a linear response in the concentration range between 7.5 pM and 100 pM with LOD and LOQ values of 2.06 pM and 6.86 pM, respectively. Anions, cations, and substances including uric acid, ascorbic acid, paracetamol, and dopamine were all used in the selectivity test. In addition, the imprinting factor (IF) study was carried out using compounds such as cefuroxime, cefazolin, cefixime, ceftazidime, and ceftriaxone, which have structural similarities with CFD, as well as impurities such as thiazolylacetyl glycine oxime (IMP-A), thiazolylacetyl glycine oxime acetal (IMP-B), and cefdinir lactone (IMP-E). The results showed that the proposed sensor was selective for CFD, as evidenced by the relative IF values of these impurities. The recovery studies of CFD were successfully applied to tablet dosage form samples, and the developed sensor demonstrated significant sensitivity and selectivity for rapid detection of CFD in tablet dosage form.
Topics: Molecularly Imprinted Polymers; Cefdinir; Electrochemical Techniques; Limit of Detection; Anti-Bacterial Agents; Molecular Imprinting; Zinc Oxide; Electrodes; Nanocomposites; Nanoparticles; Reproducibility of Results; Polymers; Tablets; Nanostructures
PubMed: 38759322
DOI: 10.1016/j.jpba.2024.116209 -
Toxicology Letters Jun 2024Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular...
Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular carcinoma. However, with the widespread use of lenvatinib, the problem of serious and fatal hepatotoxicity has become increasingly prominent. Currently, the mechanism behind this toxicity is not yet understood, and as a result, there is a lack of safe and effective intervention strategies with minimal side effects. Here, we established the model of lenvatinib-induced liver injury in vivo and in vitro and found that lenvatinib caused hepatotoxicity by inducing apoptosis. Further mechanistic studies in cellular models revealed that lenvatinib upregulated death receptor signaling pathway, which activated the downstream effector Caspase-8, and ultimately led to apoptosis. Meanwhile, lenvatinib-induced apoptosis was associated with ROS generation and DNA damage. In addition, after screening marketed drugs and natural products in combination with cellular modeling, we identified a potential co-administered drug, dabrafenib, which could alleviate lenvatinib-induced hepatotoxicity. Further mechanistic studies revealed that dabrafenib attenuated lenvatinib-induced hepatotoxicity by inhibiting the activation of the death receptor signaling pathway. Subsequently, cancer cell proliferation assays confirmed that dabrafenib did not antagonize the antitumor effects of lenvatinib. In conclusion, our results validate that apoptosis caused by the death receptor signaling pathway is the key cause of lenvatinib-induced hepatotoxicity, and dabrafenib alleviates lenvatinib-induced hepatotoxicity by inhibiting this pathway.
Topics: Quinolines; Animals; Chemical and Drug Induced Liver Injury; Oximes; Signal Transduction; Phenylurea Compounds; Humans; Apoptosis; Imidazoles; Mice; Male; Receptors, Death Domain; Antineoplastic Agents; Liver; Hep G2 Cells
PubMed: 38754640
DOI: 10.1016/j.toxlet.2024.05.004 -
PloS One 2024Recently, several randomized controlled trials (RCTs) of fluvoxamine have been successfully conducted for the treatment of patients with coronavirus disease 2019... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Recently, several randomized controlled trials (RCTs) of fluvoxamine have been successfully conducted for the treatment of patients with coronavirus disease 2019 (COVID-19). This systematic review and meta-analysis was to evaluate the efficacy and safety of fluvoxamine in patients with COVID-19.
METHODS
MEDLINE, EMBASE, Cochrane Library and clinicaltrials.gov were searched for RCTs which were performed to evaluate fluvoxamine and placebo up to January 31, 2024. Review Manager 5.3 was used to perform meta-analysis. The risk ratio (RR) and mean difference (MD) was analyzed and calculated with a random effect model.
RESULTS
We pooled 4,711 participants from six RCTs (2,382 in the fluvoxamine group and 2,329 in the placebo group). Compared to the placebo group, the fluvoxamine group had a significantly lower rate of clinical deterioration (RR, 0.73; P = 0.004; 95% CI, 0.59 to 0.90; I2 = 0%) and hospitalization (RR, 0.76; P = 0.04; 95% CI, 0.59 to 0.99; I2 = 0%). In the meantime, compared with the placebo group, fluvoxamine group did not show any higher risk of AEs (P = 0.13 and 0.91, respectively) in safety outcomes analysis. The subgroup analysis showed that fluvoxamine treatment performed more than 200 mg daily appears to be more effective than those performed less than 200 mg daily in reducing clinical deterioration and hospitalization risks, while not exhibiting higher AE and SAE risks than placebo group.
CONCLUSION
Fluvoxamine for patients with COVID-19, especially those who take 200 mg or more daily, is superior to the placebo group in reducing clinical deterioration and hospitalization, and did not show any higher risk of AEs and SAEs in safety concerns, which might be a promising intervention for COVID-19.
Topics: Fluvoxamine; Humans; COVID-19 Drug Treatment; Randomized Controlled Trials as Topic; SARS-CoV-2; COVID-19; Treatment Outcome; Hospitalization
PubMed: 38753761
DOI: 10.1371/journal.pone.0300512 -
Journal of Agricultural and Food... May 2024The discovery of structurally distinct leads is imperative in modern agrochemical science. Inspired by eudistomins Y and the framework-related pharmaceuticals, aryl...
The discovery of structurally distinct leads is imperative in modern agrochemical science. Inspired by eudistomins Y and the framework-related pharmaceuticals, aryl heteroaryl ketone was drawn as a common model intriguing the design and divergent synthesis of 14 kinds of heteroaryl ketones aligned with their oxime derivatives. Antifungal function-oriented phenotypical screen protruded benzothiazolyl-phenyl oxime as a promising model, and the concomitant modification led to benzothiazolyl oxime (EC = 5.17 μM) as a superior lead than fluoxastrobin (EC = 7.54 μM) against . Scaffold hopping of the phenyl subunit identified benzothiazolyl-pyridyl oxime as a novel antifungal scaffold accompanied by acquiring oxime with remarkable activity (EC = 3.57 μM) against . Molecular docking showed that candidate could form more hydrogen bonds with the amino acid residues of actin than metrafenone. This compound also demonstrated better curative efficacy than that of fluoxastrobin and metrafenone in controlling the plant disease caused by . These results rationalize the discovery of antifungal candidates based on aryl heteroaryl ketone.
Topics: Fungicides, Industrial; Ascomycota; Ketones; Molecular Docking Simulation; Structure-Activity Relationship; Plant Diseases; Drug Design; Molecular Structure; Oximes; Antifungal Agents
PubMed: 38753466
DOI: 10.1021/acs.jafc.3c09874 -
NPJ Systems Biology and Applications May 2024In vertical inhibition treatment strategies, multiple components of an intracellular pathway are simultaneously inhibited. Vertical inhibition of the BRAFV600E-MEK-ERK...
In vertical inhibition treatment strategies, multiple components of an intracellular pathway are simultaneously inhibited. Vertical inhibition of the BRAFV600E-MEK-ERK signalling pathway is a standard of care for treating BRAFV600E-mutated melanoma where two targeted cancer drugs, a BRAFV600E-inhibitor, and a MEK inhibitor, are administered in combination. Targeted therapies have been linked to early onsets of drug resistance, and thus treatment strategies of higher complexities and lower doses have been proposed as alternatives to current clinical strategies. However, finding optimal complex, low-dose treatment strategies is a challenge, as it is possible to design more treatment strategies than are feasibly testable in experimental settings. To quantitatively address this challenge, we develop a mathematical model of BRAFV600E-MEK-ERK signalling dynamics in response to combinations of the BRAFV600E-inhibitor dabrafenib (DBF), the MEK inhibitor trametinib (TMT), and the ERK-inhibitor SCH772984 (SCH). From a model of the BRAFV600E-MEK-ERK pathway, and a set of molecular-level drug-protein interactions, we extract a system of chemical reactions that is parameterised by in vitro data and converted to a system of ordinary differential equations (ODEs) using the law of mass action. The ODEs are solved numerically to produce simulations of how pathway-component concentrations change over time in response to different treatment strategies, i.e., inhibitor combinations and doses. The model can thus be used to limit the search space for effective treatment strategies that target the BRAFV600E-MEK-ERK pathway and warrant further experimental investigation. The results demonstrate that DBF and DBF-TMT-SCH therapies show marked sensitivity to BRAFV600E concentrations in silico, whilst TMT and SCH monotherapies do not.
Topics: Proto-Oncogene Proteins B-raf; Humans; Pyridones; MAP Kinase Signaling System; Melanoma; Imidazoles; Protein Kinase Inhibitors; Pyrimidinones; Oximes; Computer Simulation; Models, Biological; Signal Transduction; Mutation; Antineoplastic Agents; Drug Resistance, Neoplasm
PubMed: 38750040
DOI: 10.1038/s41540-024-00379-9 -
Organic Letters May 2024β-amino sulfones are important motifs found in natural products and active pharmaceutical compounds. Herein, we report a general and highly regioselective...
β-amino sulfones are important motifs found in natural products and active pharmaceutical compounds. Herein, we report a general and highly regioselective intermolecular aminosulfonylation of alkenes via the homolysis of sulfinyl oximes from ketoximes and sulfinyl chloride. This method features catalyst-free, step-efficient functionalization and prominent functional group tolerance, providing a straightforward, green, and widely applicable approach to accessing β-amino sulfone derivatives.
PubMed: 38743879
DOI: 10.1021/acs.orglett.4c01103 -
Natural Product Research May 2024Strong evidence supports the anticancer properties of natural plant product isolates. The cytotoxic, genotoxic, and apoptotic properties of an oxime derivative of...
Strong evidence supports the anticancer properties of natural plant product isolates. The cytotoxic, genotoxic, and apoptotic properties of an oxime derivative of thymoquinone (TQ) in melanoma cancer cells were investigated. The structure of TQ-Oxime was elucidated through nuclear magnetic resonance, and its effect on B16F10 and L929 cell lines was assessed using a luminometric adenosine triphosphate assay. Intracellular reactive oxygen species (iROS) were quantified fluorometry, mitochondrial membrane potential (MMP) was assessed using flow cytometry, glutathione (GSH) levels were measured using a luminometric GSH/oxidized glutathione assay, DNA damage comet assay, and apoptosis was detected using acridine orange/ethidium bromide staining. Concentrations (0.5-20 μM) of TQ-Oxime significantly increased cytotoxicity, DNA damage, apoptosis, and iROS, in a concentration-dependent manner compared ( < 0.001). In addition, MMP and GSH levels decreased significantly with increasing concentrations compared with the control ( < 0.001). Overall, these findings contribute to our understanding of the therapeutic potential of TQ and its derivatives in cancer treatment.
PubMed: 38742473
DOI: 10.1080/14786419.2024.2353913 -
Organic Letters May 2024A copper-catalyzed [3 + 2] annulation of -acyl oximes with 4-sulfonamidophenols is developed. The advantage of this method lies in the concurrent double activation of...
A copper-catalyzed [3 + 2] annulation of -acyl oximes with 4-sulfonamidophenols is developed. The advantage of this method lies in the concurrent double activation of two substrates to form nucleophilic enamines and electrophilic quinone monoimines. The substituent on the α-carbon of -acyl oxime determines two different reaction pathways, thereby leading to the selective generation of 5-sulfonamidoindoles and 2-amido-5-sulfonamidobenzofuran-3(2)-ones.
PubMed: 38738828
DOI: 10.1021/acs.orglett.4c01071