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Nature Communications Jun 2024Farmers from South Asian countries spray insecticides without protective gear, which leads to insecticide exposure through dermal and nasal routes. Acetylcholinesterase...
Oxime-functionalized anti-insecticide fabric reduces insecticide exposure through dermal and nasal routes, and prevents insecticide-induced neuromuscular-dysfunction and mortality.
Farmers from South Asian countries spray insecticides without protective gear, which leads to insecticide exposure through dermal and nasal routes. Acetylcholinesterase plays a crucial role in controlling neuromuscular function. Organophosphate and carbamate insecticides inhibit acetylcholinesterase, which leads to severe neuronal/cognitive dysfunction, breathing disorders, loss of endurance, and death. To address this issue, an Oxime-fabric is developed by covalently attaching silyl-pralidoxime to the cellulose of the fabric. The Oxime-fabric, when stitched as a bodysuit and facemask, efficiently deactivates insecticides (organophosphates and carbamates) upon contact, preventing exposure. The Oxime-fabric prevents insecticide-induced neuronal damage, neuro-muscular dysfunction, and loss of endurance. Furthermore, we observe a 100% survival rate in rats when repeatedly exposed to organophosphate-insecticide through the Oxime-fabric, while no survival is seen when organophosphate-insecticide applied directly or through normal fabric. The Oxime-fabric is washable and reusable for at least 50 cycles, providing an affordable solution to prevent insecticide-induced toxicity and lethality among farmers.
Topics: Animals; Insecticides; Rats; Oximes; Male; Pralidoxime Compounds; Textiles; Cholinesterase Inhibitors; Acetylcholinesterase; Occupational Exposure; Carbamates; Organophosphates; Administration, Intranasal
PubMed: 38844466
DOI: 10.1038/s41467-024-49167-3 -
Toxicology Mechanisms and Methods May 2021Highly toxic industrial chemicals that are widely accessible, and hazardous chemicals like phosgene oxime (CX) that can be easily synthesized, pose a serious threat as... (Review)
Review
Highly toxic industrial chemicals that are widely accessible, and hazardous chemicals like phosgene oxime (CX) that can be easily synthesized, pose a serious threat as potential chemical weapons. In addition, their accidental release can lead to chemical emergencies and mass casualties. CX, an urticant, or nettle agent, grouped with vesicating agents, causes instant pain, injury and systemic effects, which can lead to mortality. With faster cutaneous penetration, corrosive properties, and more potent toxicity compared to other vesicating agents, CX causes instantaneous and severe tissue damage. CX, a potential chemical terrorism threat agent, could therefore be weaponized with other chemical warfare agents to enhance their harmful effects. CX is the least studied vesicant and its acute and long-term toxic effects as well as its mechanism of action are largely unknown. This has hampered the identification of therapeutic targets and the development of effective medical countermeasures. There are only protective measures, decontamination, and supportive treatments available for reducing the toxic effects from CX exposure. This review summarizes CX toxicity, its known mechanism of action, and our current studies exploring the role of mast cell activation and associated signaling pathways in CX cutaneous exposure under the National Institutes of Health Countermeasures Against Chemical Threats program. Potential treatment options and the development of effective targeted countermeasures against CX-induced morbidity and mortality is also discussed.
Topics: Chemical Warfare Agents; Irritants; Oximes; Phosgene; Skin
PubMed: 33297803
DOI: 10.1080/15376516.2020.1861670 -
Journal of Agricultural and Food... Apr 2023The existing agricultural insecticides have developed drug resistance from long-term use. Isoxazoline derivatives are new insecticides discovered in the 21st century....
The existing agricultural insecticides have developed drug resistance from long-term use. Isoxazoline derivatives are new insecticides discovered in the 21st century. Because of their unique insecticidal mechanism, high selectivity, safety, and no significant cross resistance with the existing pesticides on the market, they have become a hot spot in the field of pesticide research. Herein, a series of novel isoxazoline derivatives containing ether and oxime-ether structures were designed and synthesized by a scaffold-hopping strategy using the pesticide fluralaner as a template structure. Through the investigation of insecticidal activity and the systematic structure-activity relationship, a series of compounds with high insecticidal activities were found, and compounds , , and with LC values of 0.00008-0.00036 mg/L against diamondback moth emerged as novel insecticide candidates. These compounds also exhibited broad spectrum fungicidal activities against 14 plant fungi. The current work provides a reference for the design of new isoxazoline compounds based on the scaffold-hopping strategy.
Topics: Animals; Insecticides; Ether; Oximes; Structure-Activity Relationship; Pesticides; Moths; Ethers; Ethyl Ethers; Molecular Structure; Drug Design
PubMed: 36947168
DOI: 10.1021/acs.jafc.2c08161 -
Journal of Enzyme Inhibition and... Dec 2022Different oleanolic acid (OA) oxime ester derivatives (-) were designed and synthesised to develop inhibitors against -glucosidase and -amylase. All the synthesised OA...
Different oleanolic acid (OA) oxime ester derivatives (-) were designed and synthesised to develop inhibitors against -glucosidase and -amylase. All the synthesised OA derivatives were evaluated against -glucosidase and -amylase Among them, compound showed the highest -glucosidase inhibition with an IC of 0.35 µM, which was ∼1900 times stronger than that of acarbose, meanwhile compound exhibited the highest -amylase inhibitory with an IC of 3.80 µM that was ∼26 times higher than that of acarbose. The inhibition kinetic studies showed that the inhibitory mechanism of compounds and were reversible and mixed types towards -glucosidase and -amylase, respectively. Molecular docking studies analysed the interaction between compound and two enzymes, respectively. Furthermore, cytotoxicity evaluation assay demonstrated a high level of safety profile of compounds and against 3T3-L1 and HepG2 cells.HighlightsOleanolic acid oxime ester derivatives () were synthesised and screened against α-glucosidase and α-amylase.Compound showed the highest α-glucosidase inhibitory with IC50 of 0.35 µM.Compound presented the highest α-amylase inhibitory with IC50 of 3.80 µM.Kinetic studies and studies analysed the binding between compounds and α-glucosidase or α-amylase.
Topics: Dose-Response Relationship, Drug; Enzyme Inhibitors; Esters; Humans; Molecular Structure; Oleanolic Acid; Oximes; Structure-Activity Relationship; alpha-Amylases; alpha-Glucosidases
PubMed: 35012401
DOI: 10.1080/14756366.2021.2018682 -
International Journal of Molecular... Sep 2019The application of purified enzymes as well as whole-cell biocatalysts in synthetic organic chemistry is becoming more and more popular, and both academia and industry... (Review)
Review
The application of purified enzymes as well as whole-cell biocatalysts in synthetic organic chemistry is becoming more and more popular, and both academia and industry are keen on finding and developing novel enzymes capable of performing otherwise impossible or challenging reactions. The diverse genus offers a multitude of promising enzymes, which therefore makes it one of the key bacterial hosts in many areas of research. This review focused on the broad utilization potential of the genus in organic chemistry, thereby particularly highlighting the specific enzyme classes exploited and the reactions they catalyze. Additionally, close attention was paid to the substrate scope that each enzyme class covers. Overall, a comprehensive overview of the applicability of the genus is provided, which puts this versatile microorganism in the spotlight of further research.
Topics: Biocatalysis; Catalysis; Chemistry Techniques, Synthetic; Hydrolases; Metabolic Networks and Pathways; Nitriles; Oxidation-Reduction; Oximes; Rhodococcus; Sulfur Compounds
PubMed: 31561555
DOI: 10.3390/ijms20194787 -
European Journal of Medicinal Chemistry Jan 2022Alzheimer's disease (AD) possesses a complex pathogenetic mechanism. Nowadays, multitarget agents are considered to have potential in effectively treating AD via...
Alzheimer's disease (AD) possesses a complex pathogenetic mechanism. Nowadays, multitarget agents are considered to have potential in effectively treating AD via triggering molecules in functionally complementary pathways at the same time. Here, based on the screening (∼1400 compounds) against neuroinflammation, an imidazolylacetophenone oxime ether (IOE) was discovered as a novel hit. In order to obtain SARs, a series of imidazolylacetophenone oxime derivatives were constructed, and their C=N bonds were confirmed as the Z configuration by single crystals. These derivatives exhibited potential multifunctional neuroprotective effects including anti-neuroinflammatory, antioxidative damage, metal-chelating, inhibition of acetylcholinesterase (AChE) properties. Among these derivatives, compound 12i displayed the most potent inhibitory activity against nitric oxide (NO) production with EC value of 0.57 μM 12i can dose-dependently suppress the expression of iNOS and COX-2 but not change the expression of HO-1 protein. Moreover, 12i exhibited evidently neuroprotective effects on HO-induced PC12 cells damage and ferroptosis without cytotoxicity at 10 μM, as well as selectively metal chelating properties via chelating Cu. In addition, 12i showed a mixed-type inhibitory effect on AChE in vitro. The structure-activity relationships (SARs) analysis indicated that dioxolane groups on benzene ring and rigid oxime ester can improve the activity. Parallel artificial membrane permeation assay (PAMPA) also verified that 12i can overcome the blood-brain barrier (BBB). Overall, this is the first report on imidazolylacetophenone oxime-based multifunctional neuroprotective effects, suggesting that this type of compounds might be novel multifunctional agents against AD.
Topics: Acetophenones; Acetylcholinesterase; Animals; Biphenyl Compounds; Cell Line; Cyclooxygenase 2; Dose-Response Relationship, Drug; Drug Discovery; Electrophorus; Enzyme Inhibitors; Humans; Imidazoles; Lipopolysaccharides; Mice; Molecular Structure; Neuroprotective Agents; Nitric Oxide; Oximes; Picrates; Rats; Structure-Activity Relationship
PubMed: 34875520
DOI: 10.1016/j.ejmech.2021.114031 -
Organic Letters Apr 2023The biocompatible synthesis of constrained peptides is challenging. Oxime ligation is a bioorthogonal technique frequently used for protein bioconjugation. We report a...
The biocompatible synthesis of constrained peptides is challenging. Oxime ligation is a bioorthogonal technique frequently used for protein bioconjugation. We report a straightforward method to install N-terminal ketones and aminooxy side chains during standard solid-phase peptide synthesis. Cyclization occurs spontaneously after acidic cleavage or in aqueous buffer. We demonstrate the facile synthesis of protease inhibitors with varying conformational constraint. The most constrained peptide displayed an activity 2 orders of magnitude higher than its linear analog.
Topics: Oximes; Peptides; Proteins; Solid-Phase Synthesis Techniques; Cyclization; Peptides, Cyclic
PubMed: 37053571
DOI: 10.1021/acs.orglett.3c00695 -
Archiv Der Pharmazie Jan 2021A new series of nitric oxide-donating fluoroquinolone/oximes was prepared in this study. The nitric oxide release from the prepared compounds was measured using a... (Comparative Study)
Comparative Study
A new series of nitric oxide-donating fluoroquinolone/oximes was prepared in this study. The nitric oxide release from the prepared compounds was measured using a modified Griess colorimetric method. The antitubercular evaluation of the synthesized compounds indicated that ketone derivatives 2b and 2e and oximes 3b and 3d exhibited somewhat higher activity than their respective parent fluoroquinolones. Mycobacterial DNA cleavage studies and molecular modeling of Mycobacterium tuberculosis DNA gyrase were pursued to explain the observed bioactivity. More important, antibacterial evaluation showed that oximes 3c-e are highly potent against Klebsiella pneumoniae, with minimum inhibitory concentration (MIC) values of 0.06, 0.08, and 0.034 µM, respectively, whereas ketone 2c and oxime 4c are more active against Staphylococcus aureus than ciprofloxacin (MIC values: 0.7, 0.38, and 1.6 µM, respectively). Notably, the antipseudomonal activities of compounds 2a and 4c were much higher than those of their respective parent fluoroquinolones.
Topics: Anti-Bacterial Agents; Antitubercular Agents; Bacteria; Ciprofloxacin; Fluoroquinolones; Microbial Sensitivity Tests; Models, Molecular; Nitric Oxide; Nitric Oxide Donors; Oximes; Structure-Activity Relationship
PubMed: 32959443
DOI: 10.1002/ardp.202000180 -
Journal of the American Chemical Society Dec 2021Post-translational modifications (PTMs) of proteins are a biological mechanism for reversibly controlling protein function. Synthetic protein modifications (SPMs) at...
Post-translational modifications (PTMs) of proteins are a biological mechanism for reversibly controlling protein function. Synthetic protein modifications (SPMs) at specific canonical amino acids can mimic PTMs. However, reversible SPMs at hydrophobic amino acid residues in proteins are especially limited. Here, we report a tyrosine (Tyr)-selective SPM utilizing persistent iminoxyl radicals, which are readily generated from sterically hindered oximes via single-electron oxidation. The reactivity of iminoxyl radicals with Tyr was dependent on the steric and electronic demands of oximes; isopropyl methyl piperidinium oxime formed stable adducts, whereas the reaction of -butyl methyl piperidinium oxime was reversible. The difference in reversibility between and , differentiated only by one methyl group, is due to the stability of iminoxyl radicals, which is partly dictated by the bond dissociation energy of oxime O-H groups. The Tyr-selective modifications with and proceeded under physiologically relevant, mild conditions. Specifically, the stable Tyr-modification with introduced functional small molecules, including an azobenzene photoswitch, to proteins. Moreover, masking critical Tyr residues by SPM with , and subsequent deconjugation triggered by the treatment with a thiol, enabled on-demand control of protein functions. We applied this reversible Tyr modification with to alter an enzymatic activity and the binding affinity of a monoclonal antibody with an antigen upon modification/deconjugation. The on-demand ON/OFF switch of protein functions through Tyr-selective and reversible covalent-bond formation will provide unique opportunities in biological research and therapeutics.
Topics: Amino Acid Sequence; Animals; Canavalia; Cattle; Chickens; Free Radicals; Humans; Imines; Oximes; Peptides; Proteins; Tyrosine
PubMed: 34787412
DOI: 10.1021/jacs.1c09066 -
Molecules (Basel, Switzerland) Jun 2023The -Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including cell proliferation and differentiation,...
The -Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including cell proliferation and differentiation, cell survival, and inflammation. Because of emerging data suggesting that JNK3 may play an important role in neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease, as well as cancer pathogenesis, we sought to identify JNK inhibitors with increased selectivity for JNK3. A panel of 26 novel tryptanthrin-6-oxime analogs was synthesized and evaluated for JNK1-3 binding (K) and inhibition of cellular inflammatory responses. Compounds (8-methoxyindolo[2,1-]quinazolin-6,12-dione oxime) and (8-phenylindolo[2,1-]quinazolin-6,12-dione oxime) had high selectivity for JNK3 versus JNK1 and JNK2 and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in THP-1Blue cells and interleukin-6 (IL-6) production by MonoMac-6 monocytic cells in the low micromolar range. Likewise, compounds , , and pan-JNK inhibitor (9-methylindolo[2,1-]quinazolin-6,12-dione oxime) decreased LPS-induced -Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of these compounds in the JNK3 catalytic site that were in agreement with the experimental data on JNK3 binding. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems with selectivity for JNK3.
Topics: JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Mitogen-Activated Protein Kinase 8; Phosphorylation; Oximes
PubMed: 37375361
DOI: 10.3390/molecules28124806