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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 -
Acta Biomaterialia Apr 2021Biotherapeutics have achieved global economic success due to their high specificity towards their drug targets, providing exceptional safety and efficiency. The ongoing...
Biotherapeutics have achieved global economic success due to their high specificity towards their drug targets, providing exceptional safety and efficiency. The ongoing shift away from small molecule drugs towards biotherapeutics heightens the need to further improve the pharmacokinetics of these biological drugs. Three pervasive obstacles that limit the therapeutic capacity of biotherapeutics are proteolytic degradation, circulating half-life, and the development of anti-drug antibodies. These challenges can culminate in limited efficiency and consequently warrant the need for higher drug doses and more frequent administration. We have explored the coupling of biotherapeutics to long-lived and biocompatible red blood cells (RBCs) to address limited pharmacokinetics. Butyrylcholinesterase (BChE), for example, provides prophylactic protection against organophosphate nerve agents (OPNAs), yet the short circulation life of the drug requires extraordinary doses. Herein, we report the rapid and tunable chemical engineering of BChE to RBC membranes to create a cell-based delivery system that retains the enzyme activity and enhances stability. In a three-step process that first pre-modifies BChE with a cell-reactive polymer chain, primes the cells for engineering, and then grafts the conjugates to the cells, we attached over 2 million BChE molecules to the surface of each RBC without diminishing the bioscavenging capacity of the enzyme. Critically, this membrane-engineering approach was cell-tolerated with minimal hemolysis observed. These results provide strong evidence for the ability of engineered RBCs to serve as an enhanced biotherapeutic delivery vehicle. STATEMENT OF SIGNIFICANCE: Organophosphate nerve agents (OPNAs) are one of the most lethal forms of chemical warfare. After exposure to OPNAs, a patient is given life-saving therapeutics, such as atropine and oxime. However, these drugs are limited, and the patient can still suffer from irreparable injuries. Given the toxicity of OPNAs, access to a prophylactic is vital. We have created an enhanced delivery system for prophylactic butyrylcholinesterase (BChE) by engineering this biotherapeutic to the red blood cell (RBC) surface. In three simple steps that first pre-modifies BChE with a cell-reactive polymer, primes the cells for engineering, and then grafts the conjugates to the cells, we attached over 2 million BChE molecules to a single RBC while retaining the enzyme's activity and enhancing its stability.
Topics: Butyrylcholinesterase; Erythrocytes; Humans; Organophosphates; Oximes; Pharmaceutical Preparations
PubMed: 33529769
DOI: 10.1016/j.actbio.2021.01.043 -
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 -
Molecules (Basel, Switzerland) Feb 2023Steroids and their derivatives have been the subject of extensive research among investigators due to their wide range of pharmacological properties, in which steroidal... (Review)
Review
Steroids and their derivatives have been the subject of extensive research among investigators due to their wide range of pharmacological properties, in which steroidal oximes are included. Oximes are a chemical group with the general formula RRC=N-OH and they exist as colorless crystals and are poorly soluble in water. Oximes can be easily obtained through the condensation of aldehydes or ketones with various amine derivatives, making them a very interesting chemical group in medicinal chemistry for the design of drugs as potential treatments for several diseases. In this review, we will focus on the different biological activities displayed by steroidal oximes such as anticancer, anti-inflammatory, antibacterial, antifungal and antiviral, among others, as well as their respective mechanisms of action. An overview of the chemistry of oximes will also be reported, and several steroidal oximes that are in clinical trials or already used as drugs are described. An extensive literature search was performed on three main databases-PubMed, Web of Science, and Google Scholar.
Topics: Oximes; Steroids; Anti-Bacterial Agents; Antifungal Agents; Antiviral Agents
PubMed: 36838678
DOI: 10.3390/molecules28041690 -
Natural Product Research Apr 2020Incorporation of the Beckmann rearrangement into the presented research resulted in the formation of nitrogen-containing terpenoid derivatives originating from naturally...
Incorporation of the Beckmann rearrangement into the presented research resulted in the formation of nitrogen-containing terpenoid derivatives originating from naturally occurring compounds. Both starting monoterpenes and obtained derivatives were subjected to estimation of their antibacterial potential. In the presented study, was the most sensitive to examined compounds. The Minimal Inhibitory Concentration (MIC) experiments performed on demonstrated that the (-)-menthone oxime and (+)-pulegone oxime had the best antibacterial activity among the tested derivatives and starting compounds. Their MIC value was 100 µg/mL. The obtained derivatives were also evaluated for their inhibitory activity against bacterial urease. Among the tested compounds, three active inhibitors were found - oxime and lactams and limited the activity of urease with values of 174.3 µM, 43.0 µM and 4.6 µM, respectively. To our knowledge, derivative is the most active antiureolytic lactam described to date.
Topics: Anti-Bacterial Agents; Cyclohexane Monoterpenes; Lactams; Menthol; Microbial Sensitivity Tests; Monoterpenes; Nitrogen; Oximes; Staphylococcus aureus; Urease
PubMed: 30663357
DOI: 10.1080/14786419.2018.1548456 -
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 -
Accounts of Chemical Research Sep 2022A radical shift toward energy transfer photocatalysis from electron transfer photocatalysis under visible-light photoirradiation is often due to the greener prospects of...
A radical shift toward energy transfer photocatalysis from electron transfer photocatalysis under visible-light photoirradiation is often due to the greener prospects of atom and process economy. Recent advances in energy transfer photocatalysis embrace unique strategies for direct small-molecule activation and sometimes extraordinary chemical bond formation in the absence of additional/sacrificial reagents. Selective energy transfer photocatalysis requires careful selection of substrates and photocatalysts for a perfect match with respect to their triplet energies while having incompatible redox potentials to prevent competitive electron transfer pathways. Substrates containing labile N-O bonds are potential targets for generating reactive key intermediates via photocatalysis to access a variety of functionalized molecules. Typically, the differential electron densities of N and O heteroatoms have been exploited for generation of either N- or O-centered radical intermediates from the functionalized substrates by the electron transfer pathway. However, the latest developments involve direct N-O bond homolysis via energy transfer to generate both N- and O-centered radicals for their subsequent utilization in diverse organic transformations, also in the absence of sacrificial redox reagents. In this Account, we highlight our key contributions in the field of N-O bond activation via energy transfer photocatalysis to generate reactive radical intermediates, with coverage of useful mechanistic insights. More specifically, well-designed N-O bond-containing substrates such as 1,2,4-oxadiazolines, oxime esters, -indolyl carbonates, and -enoxybenzotriazoles were successfully utilized in versatile transformations involving selective energy transfer over electron transfer from photocatalysts with high triplet state energy. Direct access to reactive N-, O-, and C-centered (if decarboxylation follows) radical intermediates was achieved for diverse cross-couplings and rearrangement processes. In particular, a variety of open-shell nitrogen reactive intermediates, including N(sp) and N(sp) radicals and nitrenes, have been utilized. Notably, diversified transformations of identical substrates have been achieved through careful control of the reaction conditions. 1,2,4-Oxadiazolines were converted into spiro-azolactams through iminyl intermediates in the presence of O, benzimidazoles, or sulfoximines with external sulfoxide reagent through triplet nitrene intermediates under inert conditions. Besides, oxime esters underwent either intramolecular C(sp)-N radical-radical coupling or intermolecular C(sp)-N radical-radical coupling by a combined energy transfer-hydrogen atom transfer strategy. Furthermore, a series of electrochemical and photophysical experiments as well as computational studies were performed to substantiate the proposed selective energy-transfer-driven reaction pathways. We hope that this Account will serve as a guide for the rational design of selective energy transfer processes through the activation of further labile chemical bonds.
Topics: Energy Transfer; Esters; Hydrogen; Oxidation-Reduction; Oximes
PubMed: 35986693
DOI: 10.1021/acs.accounts.2c00444 -
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