-
Chemico-biological Interactions Nov 2017Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little...
Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound's PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t of ∼1 h. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The C in the brain ranged between 0.03 and 0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.
Topics: Acetamides; Acetylcholinesterase; Animals; Blood-Brain Barrier; Cholinesterase Reactivators; Guinea Pigs; Kidney; Male; Oximes; Tissue Distribution
PubMed: 28941624
DOI: 10.1016/j.cbi.2017.09.016 -
Bioorganic Chemistry Nov 2021Infections caused due to multidrug resistant organisms have emerged as a constant menace to human health. Even though numerous antibiotics are currently available for...
Infections caused due to multidrug resistant organisms have emerged as a constant menace to human health. Even though numerous antibiotics are currently available for treating infectious diseases, a great number of bacterial strains have acquired resistance to many of them. Among these, infections caused due to Staphylococcus aureus are predominant in adult and paediatric population. Indole is a prominent chemical scaffold found in many pharmacologically active natural products and synthetic drugs. A number of oxime ether containing compounds have attracted attention of researchers owing to their interesting biological properties. Current work details the synthesis of indole containing oxime ether derivatives and their evaluation for antimicrobial activity against a panel of bacterial and mycobacterial strains. Synthesized compounds demonstrated good to moderate activity against drug-resistant S. aureus including resistant to vancomycin. Among all, compound 5h was found to possess potent activity against susceptible as well as MRSA and VRSA strains of S. aureus with MIC of 1 µg/mL and 2-4 µg/mL respectively. In addition, compound 5h was found to be non-toxic to Vero cells and exhibited good selectivity index of >40. Further, 5h, E-9a and E-9b possessed good biofilm inhibition against S. aureus. With these assuring biological properties, synthesized compounds could be potential prospective antimicrobial agents.
Topics: Animals; Anti-Bacterial Agents; Biofilms; Chlorocebus aethiops; Dose-Response Relationship, Drug; Methicillin Resistance; Microbial Sensitivity Tests; Molecular Structure; Oximes; Staphylococcus aureus; Structure-Activity Relationship; Vancomycin Resistance; Vero Cells
PubMed: 34454299
DOI: 10.1016/j.bioorg.2021.105288 -
Lancet (London, England) Sep 1971
Topics: Female; Humans; Infusions, Parenteral; Injections, Intramuscular; Middle Aged; Oximes; Tetanus; Tetanus Antitoxin
PubMed: 4105966
DOI: 10.1016/s0140-6736(71)80095-8 -
European Journal of Medicinal Chemistry Apr 2013Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking...
Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking activities were evaluated by a JC-1 assay, measuring the change of mitochondrial membrane potential. The inhibitory activity of nine compounds against amyloid beta-induced mPTP opening was comparable or even superior to that of piracetam. Among them, 12d effectively maintained mitochondrial function and cell viabilities on the ATP assay, the MTT assay, and the ROS assay. In addition, it exhibited favorable in vitro stability and pharmacokinetic characteristics, which hold a promise for further development of AD therapeutics.
Topics: Amyloid beta-Peptides; Animals; Cells, Cultured; Humans; Male; Mice; Mice, Inbred ICR; Mitochondria; Mitochondrial Membranes; Molecular Structure; Oximes; Rats; Rats, Sprague-Dawley
PubMed: 23353734
DOI: 10.1016/j.ejmech.2012.12.033 -
Acta Poloniae Pharmaceutica 1977
Topics: Indicators and Reagents; Oximes; Parasympatholytics
PubMed: 930610
DOI: No ID Found -
Bioorganic & Medicinal Chemistry Letters Aug 2017Inspired by the significant anti-cancer activity of our previously screened natural ergosterol peroxide (EP, 1), we synthesized and characterized a series of novel...
Inspired by the significant anti-cancer activity of our previously screened natural ergosterol peroxide (EP, 1), we synthesized and characterized a series of novel 5α,8α-epidioxyandrost-3β-ol-17-(O-phenylacetamide)oxime derivatives (9a-o). The anti-proliferative activity of the synthesized compounds against human hepatocellular carcinoma cells (HepG2, Sk-Hep1) and human breast cancer cells (MCF-7, MDA-MB231) were investigated. Compounds 9d, 9f, 9h, 9j and 9m displayed good anti-proliferative activity (most IC<20μM) in vitro. Furthermore, fluorescence imaging showed that the designed coumarin-9d conjugate (12) localized mainly in mitochondria, leading to enhanced anticancer activities over the parent structure.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Structure; Oximes; Structure-Activity Relationship
PubMed: 28666736
DOI: 10.1016/j.bmcl.2017.06.048 -
Journal of Applied Toxicology : JAT 1994A review was conducted of papers describing the use of N-methyl-2-pyridinealdoxime (PAM), toxogonin or HI-6 as antidotes to the nerve agents tabun, sarin, soman and VX.... (Review)
Review
A review was conducted of papers describing the use of N-methyl-2-pyridinealdoxime (PAM), toxogonin or HI-6 as antidotes to the nerve agents tabun, sarin, soman and VX. The review included use of the oxime alone, oxime plus atropine and oxime plus atropine plus diazepam, given therapeutically, i.e. after nerve agent, in all cases. Experiments with any of these compounds given prophylactically were not considered. The review also included protocols of pyridostigmine prophylaxis and oxime-atropine therapy (with or without diazepam). It was difficult to draw conclusions as to the best oxime to use, because of lack of data in many cases. The identity of the oxime did not appear to be important when pyridostigmine prophylaxis was combined with atropine-oxime-diazepam therapy; in these cases, very good protection was observed in guinea pigs against all four nerve agents. The choice of oxime based on the data presently available may well depend on factors other than protection against lethality, such as cost and availability of the oxime and human toxicity of the oxime. This last factor was also reviewed, and the results showed that toxogonin is likely to cause more side-effects than PAM or HI-6. The efficacy of the oximes against the emerging threat agent GF was also reviewed.
Topics: Animals; Antidotes; Chemical Warfare Agents; Cholinesterase Inhibitors; Humans; Nervous System Diseases; Oximes
PubMed: 7822680
DOI: 10.1002/jat.2550140502 -
Molecules (Basel, Switzerland) Nov 2021Gastrointestinal tract infection caused by is a common virulent disease found worldwide, and the infection rate is much higher in developing countries than in developed...
Gastrointestinal tract infection caused by is a common virulent disease found worldwide, and the infection rate is much higher in developing countries than in developed ones. In the pathogenesis of in the gastrointestinal tract, the secretion of the urease enzyme plays a major role. Therefore, inhibition of urease is a better approach against infection. In the present study, a series of syn and anti isomers of -substituted indole-3-carbaldehyde oxime derivatives was synthesized via Schiff base reaction of appropriate carbaldehyde derivatives with hydroxylamine hydrochloride. The in vitro urease inhibitory activities of those derivatives were evaluated against that of urease using the modified Berthelot reaction. Out of the tested compounds, compound (IC = 0.0516 ± 0.0035 mM) and compound (IC = 0.0345 ± 0.0008 mM) were identified as the derivatives with potent urease inhibitory activity with compared to thiourea (IC = 0.2387 ± 0.0048 mM). Additionally, in silico studies for all oxime compounds were performed to investigate the binding interactions with the active site of the urease enzyme compared to thiourea. Furthermore, the drug-likeness of the synthesized oxime compounds was also predicted.
Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Enzyme Inhibitors; Helicobacter pylori; Indoles; Microbial Sensitivity Tests; Molecular Structure; Oximes; Stereoisomerism; Urease
PubMed: 34771067
DOI: 10.3390/molecules26216658 -
Drug Development Research Mar 2019In this study, 15 new oxime ether derivatives were synthesized and their anticonvulsant activities were screened in vivo. The compounds were synthesized by the reaction...
In this study, 15 new oxime ether derivatives were synthesized and their anticonvulsant activities were screened in vivo. The compounds were synthesized by the reaction of various alkyl halides with 1-(2-naphthyl)-2-(1H-imidazol-1-yl)ethanone oxime. Their anticonvulsant activities were determined using acute (maximal electroshock, subcutaneous metrazol [SCM], and 6 Hz seizure test) and chronic (corneal-kindled mouse) seizure models, their neurotoxic effects were evaluated by models of behavioral toxicity according to the Epilepsy Therapy Screening Program protocol of the NIH. All our compounds were protective in at least one of the tests. Quantification studies were applied to some of the active compounds and the intraperitoneal ED values in mice were found between 25.48 and 99.56 mg/kg. Some pharmacokinetic properties of the compounds were predicted in silico and molecular docking studies were performed to provide insights into their possible anticonvulsant mechanism regarding their SCM activity.
Topics: Animals; Anticonvulsants; Imidazoles; Male; Mice; Models, Molecular; Oximes; Receptors, GABA-A; Seizures; Structure-Activity Relationship
PubMed: 30474215
DOI: 10.1002/ddr.21491 -
Molecules (Basel, Switzerland) Jun 2024In this research, with an aim to develop novel pyrazole oxime ether derivatives possessing potential biological activity, thirty-two pyrazole oxime ethers, including a...
In this research, with an aim to develop novel pyrazole oxime ether derivatives possessing potential biological activity, thirty-two pyrazole oxime ethers, including a substituted pyridine ring, have been synthesized and structurally identified through H NMR, C NMR, and HRMS. Bioassay data indicated that most of these compounds owned strong insecticidal properties against , , , and at a dosage of 500 μg/mL, and some title compounds were active towards at 500 μg/mL. Furthermore, some of the designed compounds had potent insecticidal effects against , , or at 100 μg/mL, with the mortalities of compounds , , , , , , , , , , and against , in particular, all reaching 100%. Even when the dosage was lowered to 20 μg/mL, compound also expressed 50% insecticidal activity against , and compounds , , , , , and displayed more than 60% inhibition rates against . The current results provided a significant basis for the rational design of biologically active pyrazole oxime ethers in future.
Topics: Pyrazoles; Oximes; Insecticides; Animals; Drug Design; Structure-Activity Relationship; Ethers; Molecular Structure; Pyridines; Moths
PubMed: 38930832
DOI: 10.3390/molecules29122767