Oxime Compounds Research Articles

Synthesis of 4-Hydroxyindolin-2-ones via Phosphoric Acid-Mediated Annulation of β-Nitrostyrenes with 1,3-Cyclohexanedione.

The efficient synthesis of 4-hydroxy-3-arylindolin-2-ones via phosphoric acid-mediated annulation of various β-nitrostyrenes and 1,3-cyclohexanedione is described. This annulation reaction gives a practical method for affording a diverse set of oxindoles, having simple experimentation, readily available starting materials, and very good yields. Additionally, substituted 1,3-cyclohexanediones under the same conditions afforded tetrahydrobenzofuran oxime compounds.

QSAR modeling for cytotoxicity of sulfur-containing Shikonin oxime derivatives targeting HCT-15, MGC-803, BEL-7402, and MCF-7 cell lines

Targeting cancer cells through drug-based treatment or combination therapy protocols involving chemical compounds can be challenging due to multiple factors, including their resistance to bioactive compounds and the potential of drugs to damage healthy cells. This study aims to investigate the relationship between the structure of novel sulfur-containing shikonin oxime compounds and the corresponding cytotoxicity against four cancer types, namely colon, gastric, liver, and breast cancers, through computational chemistry tools. This investigation is suggested to help build insights into how the structure of the compounds influences their activity and understand the mechanisms behind it and subsequently might be used in multi-cancer drug design process to propose novel optimized compounds that potentially exhibit the desired activity. The findings showed that the cytotoxic activity against the four cancer types was accurately predictable (R2 > 0.7, NRMSE <20%) by a combination of search and machine learning algorithms, based on the information on the structure of the compounds, including their lipophilicity, surface area, and volume. Overall, this study is supposed to play a crucial role in effective multi-cancer drug design in cancer research areas.

Synthesis of bilaterally thiadiazole substituted vic-dioxime ligands and investigation of their polymeric metal complexes

In this study, three novels substituted 1,3,4-thiadiazole-derived vic-dioxime ligands and their corresponding polymeric transition metal (Co2+and Ni2+) complexes were synthesized and their structural characterizations were performed. For this purpose, 4,4′-bis(chloroacetyldiphenyl) ether (OKS1) was obtained from the reaction of diphenyl ether with chloroacetyl chloride at a 1:2 molar ratio with the help of the Friedel-Crafts reaction. Our first starting oxime compound “2,2′-(oxybis(4,1-phenylene))bis(N‑hydroxy-2-oxoacetimidoyl) chloride (OKS2)” was obtained from the reaction of OKS1 with butyl nitrite at a 1:2 molar ratio under the catalysis of HCl gas. Then, our final starting vic-dioxime compound “2,2′-(oxybis(4,1-phenylene))bis(N‑hydroxy-2-(hydroxyimino) acetimidoyl) chloride (OKS3)” was obtained from the reaction of OKS2 with hydroxylamine hydrochloride in ethanol media at 40 °C. Then, our three original target vic-dioxime compounds (OKL1-OKL3) were synthesized from the reaction of substituted 2-amino-1,3,4-thiadiazole compounds with OKS3. Structural characterizations of all synthesized organic compounds were made using elemental analysis, FTIR, 1H and 13C NMR and mass spectroscopy methods. Target complexes were obtained from the reaction of all ligands with MCl2.nH2O (M: Co2+and Ni2+) salts, and their structures were elucidated using FTIR, magnetic susceptibility, thermogravimetric analysis, elemental analysis, and ICP-OES spectroscopy methods.

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics.

New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain-blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents-sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's.

Discovery of (E)-2-(hydroxyimino)-N-(2 ((4methylpentyl)amino)ethyl)acetamide (KR-27425) as a non-pyridinium oxime reactivator of paraoxon-inhibited acetylcholinesterase

This study aimed to explore non-pyridinium oxime acetylcholinesterase (AChE) reactivators that could hold the potential to overcome the limitations of the currently available compounds used in the clinic to treat the neurologic manifestations induced by intoxication with organophosphorus agents. Fifteen compounds with various non-pyridinium oxime moieties were evaluated for AChE activity at different concentrations, including aldoximes, ketoximes, and α-ketoaldoximes. The therapeutic potential of the oxime compounds was evaluated by assessing their ability to reactivate AChE inhibited by paraoxon. Among the tested compounds, α-Ketoaldoxime derivative 13 showed the highest reactivation (%) reaching 67 % and 60 % AChE reactivation when evaluated against OP-inhibited electric eel AChE at concentrations of 1,000 and 100 μM, respectively. Compound 13 showed a comparable reactivation ability of AChE (60 %) compared to that of pralidoxime (56 %) at concentrations of 100 μM. Molecular docking simulation of the most active compounds 12 and 13 was conducted to predict the binding mode of the reactivation of electric eel AChE. As a result, a non-pyridinium oxime moiety 13, is a potential reactivator of OP-inhibited AChE and is taken as a lead compound for the development of novel AChE reactivators with enhanced capacity to freely cross the blood–brain barrier.

EFFICACY OF A DCBRN-01VN SKIN DECONTAMINANT ON ANIMALS EXPOSED TO 2-CHLOROETHYL ETHYL SULFIDE

Chemical warfare agents are an actual threat and decontamination for victims is a main concern when mass exposure occurs. The study evaluated the effectiveness of the skin decontamination agent DCBRN-01VN based on the oxime compound KBDO for CEES (2-chloroethyl ethyl sulfide). HPLC analysis method was used to determine the temperature after decontamination in vitro and in vivo tests and then to check biochemical and hematological indicators in rats. The test results show that DCBRN-01VN has a high efficiency of CEES decontamination, in vitro: with the ratio of CEES: decontaminant 1:20 in 10 minutes reaching 55.04%, with the ratio 1:10 in 20 minutes reached 55.95%, in 30 minutes reached 82.93%, in 60 minutes reached nearly 100%; in vivo test with a ratio of 1:15 in 20 minutes reached almost 100%. Results of biochemical and hematological examination showed no difference between the negative control group and two experimental groups (with decontamination and without decontamination) P(2-1) &gt; 0.05; P(3-1) &gt; 0.05. Histopathological analysis showed that decontamination also reduced damage caused by CEES.

Biologically active secoiridoids: A comprehensive update.

Secoiridoids are natural products of cyclopentane monoterpene derivatives that are formed by splitting the rings of cyclomethene oxime compounds at C-7 and C-8, and only account for a small part of cyclic ether terpenoids. Because of the chemically active hemiacetal structure in their common basic skeleton, secoiridoids have a wide range of biological activities, such as neuroprotective, anti-inflammatory, antidiabetic, hepatoprotective, and antinociceptive activities. Phenolic secoiridoids can also act against multiple molecular targets involved in human tumorigenesis, making them potentially valuable precursors for antitumor drug development. This review provides a detailed update, covering relevant discoveries from January 2011 to December 2020, about the occurrence, structural diversity, bioactivities, and synthesis of naturally occurring secoiridoids. We aimed to resolve the lack of extensive, specific, and thorough review of secoiridoids, as well as open new areas for pharmacological investigation and better drugs based on these compounds.

High performance supercapacitive behaviors of oximes in a poly(aniline-co-pyrrole) based conducting polymer structure

Novel oxime compounds and their complexes were synthesized and used as additives to poly(aniline-co-pyrrole) for the first time in the literature.

Structure-activity relationships of oxime compounds as flotation collectors by DFT calculations

The relationships between the structure of oxime compounds (R1R2C=NOH, R1/R2=alkyl groups) with different substituents and their corresponding flotation performances were studied. The analyses of density functional theory (DFT) calculations illustrated that the introduced phenyl group at the R1 position could enhance the acidity, while the heptyl group could effectively increase the hydrophobicity and benefit van der Waals interactions. Meanwhile, the introduced amino group at the R2 position could provide cationic sites to interact with negatively charged surfaces of minerals, while the introduced hydroxyl group could provide additional action sites to form stable chelates with metal ions. Based on the structure-activity relationships, structural optimization was carried out to obtain three efficient collectors, which possessed superior flotation separation performances, proving the effectiveness of the structural modification to oxime compounds in this work.

Vortex-assisted restricted access-based supramolecular solvent microextraction of trace Pb(II) ions with 4-(benzimidazolisonitrosoacetyl)biphenyl as a complexing agent before microsampling flame AAS analysis

A new oxime compound, 4-(benzimidazolisonitrosoacetyl)biphenyl (BIBP) was synthesized and used as a complexing agent in this study to preconcentrate trace amounts of Pb(II) ions with vortex-assisted restricted access-based supramolecular solvent microextraction (RA/SUPRAS-LPME) method. The new complexing agent was characterized by a combination of elemental analyses, Proton Nuclear Magnetic Resonance (1H- NMR), Carbon-13 Nuclear Magnetic Resonance (13C NMR) and Fourier Transform Infrared spectroscopy (FT-IR) and techniques. Extraction of the complex which was formed at pH 8.0 was done by using a supramolecular solvent phase of tetrahydrofuran (THF) and 1-decanol. A microsampling flame atomic absorption spectrophotometer was used to measure the lead ion concentrations of the extract. The method optimized and the optimum experimental conditions were found as; pH = 8, amount of the ligand 2,25 mg, supramolecular solvent volume 50 μL, sample volume 20 mL and vortex time 3 min. The limit of detection (LOD), limit of quantification (LOQ) were calculated as 0.69 μg L−1 and 2.29 μg L−1, respectively. Linear range was found between 15.1 μg L−1 and 606 μg L−1. The developed method was applied to Pb(II) determination in real samples after evaluating the accuracy by using the TMDA-53.3 fortified environmental water sample as certified reference material.

Orthopalladated tetralone oxime compounds bearing tertiary phosphines: Synthesis, structure, biological and in silico studies

The halido-α-bridge cleavage reactions between [Pd(C2,N-tetrox)(μ-Cl)]2 precursor (tetrox = E-α-tetralone oxime) with phosphines, in 1:2 molar ratio, have afforded mononuclear cyclopalladated compounds of the type [PdCl(C2,N-tetrox)(L)] {L = triphenylphosphine (1); tris(4-methylphenyl)phosphine (2); tris(4-fluorophenyl)phosphine (3) and tris(4-methoxyphenyl)phosphine (4)}. The compounds have been characterized by elemental analyses, infrared (FT-IR) and 1H, 13C{1H} and 31P{1H}-NMR spectroscopies. The molecular structure of 3 has been determined by single crystal X-ray diffraction (SC-XRD) and the Hirshfeld Surface calculation (HS) has been performed. The antiproliferative activity of compounds 1–4 has been evaluated against breast (MCF-7) and lung (A549) human cancer cells, and human lung fibroblast (MRC-5). All cyclopalladated compounds have been more active than cisplatin against MCF-7 cells, with IC50 values ranging from 19 to 26 µM. Binding experiments involving compound 3 with ct-DNA and human serum albumin (HSA) have been carried out using spectroscopic techniques. The interaction between compound 3 and HSA has been studied by means of molecular docking.

Synthesis, In Silico Studies, and Evaluation of Syn and Anti Isomers of N-Substituted Indole-3-carbaldehyde Oxime Derivatives as Urease Inhibitors against Helicobacter pylori.

Gastrointestinal tract infection caused by Helicobacter pylori 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 H. pylori in the gastrointestinal tract, the secretion of the urease enzyme plays a major role. Therefore, inhibition of urease is a better approach against H. pylori infection. In the present study, a series of syn and anti isomers of N-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 Macrotyloma uniflorum urease using the modified Berthelot reaction. Out of the tested compounds, compound 8 (IC50 = 0.0516 ± 0.0035 mM) and compound 9 (IC50 = 0.0345 ± 0.0008 mM) were identified as the derivatives with potent urease inhibitory activity with compared to thiourea (IC50 = 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.

Caged Oxime Reactivators Designed for the Light Control of Acetylcholinesterase Reactivation†.

Despite its promising role in the active control of biological functions by light, photocaging remains untested in acetylcholinesterase (AChE), a key enzyme in the cholinergic family. Here, we describe synthesis, photochemical properties and biochemical activities of two caged oxime compounds applied in the photocontrolled reactivation of the AChE inactivated by reactive organophosphate. Each of these consists of a photocleavable coumarin cage tethered to a known oxime reactivator for AChE that belongs in an either 2-(hydroxyimino)acetamide or pyridiniumaldoxime class. Of these, the first caged compound was able to successfully go through oxime uncaging upon irradiation at long-wavelength ultraviolet light (365 nm) or visible light (420 nm). It was further evaluated in AChE assays invitro under variable light conditions to define its activity in the photocontrolled reactivation of paraoxon-inactivated AChE. This assay result showed its lack of activity in the dark but its induction of activity under light conditions only. In summary, this article reports a first class of light-activatable modulators for AChE and it offers assay methods and novel insights that help to achieve an effective design of caged compounds in the enzyme control.

Synthesis, characterization and antioxidant activities of some novel oxime derivatives

In this study, nine novel compounds were synthesized in the reaction of ω-chloroisonitrosoacetophenone with 2-chloro-4-methylaniline, 2-chloro-5-methylaniline, 2-chloro-6-methylaniline, 3-chloro-2-methylaniline, 4-chloro-3-methylaniline, 5-chloro2-methylaniline, 2,3-dichloroaniline, 2,4-dichloroaniline and 3,5-dichloroaniline resulting for C1-C9, respectively. Compounds C1, C4-C7 and C9 were handled in single crystalline forms, which the structures were also investigated by X-ray single crystal analysis. Compounds were evaluated for their nonenzymatic lipid peroxidation inhibition, antioxidant and antiradical activities and compared with standard agents at 5, 50, and 100μM concentrations. Compounds are exhibited good antioxidant activities and lipid peroxidation compared to standards (BHA, TBHQ, BHT and trolox). Due to the best of our knowledge for novel oxime compounds, this study is the first report of promising antioxidants to scavenge oxidative stress conditions.

Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase.

Poisoning with organophosphorus compounds used as pesticides or misused as chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase and butyrylcholinesterase, which causes overstimulation of the cholinergic system and often leads to serious injury or death. Treatment of organophosphorus poisoning involves, among other strategies, the administration of oxime compounds. Oximes reactivate cholinesterases by breaking the covalent bond between the serine residue from the enzyme active site and the phosphorus atom of the organophosphorus compound. Although the general mechanism of reactivation has been known for years, the exact molecular aspects determining the efficiency and selectivity of individual oximes are still not clear. This hinders the development of new active compounds. In our research, using relatively simple and widely available molecular docking methods, we investigated the reactivation of acetyl- and butyrylcholinesterase blocked by sarin and tabun. For the selected oximes, their binding modes at each step of the reactivation process were identified. Amino acids essential for effective reactivation and those responsible for the selectivity of individual oximes against inhibited acetyl- and butyrylcholinesterase were identified. This research broadens the knowledge about cholinesterase reactivation and demonstrates the usefulness of molecular docking in the study of this process. The presented observations and methods can be used in the future to support the search for new effective reactivators.

Visible-light-mediated cascade cyanoalkylsulfonylation/cyclization of alkynoates leading to coumarins via SO2 insertion.

A visible-light-mediated tandem cyanoalkylsulfonylation/cyclization of alkynoates with cycloketone oxime compounds for the preparation of 3-cyanoalkylsulfonylcoumarins via SO2 insertion is reported. The difunctionalization of carbon-carbon triple bonds includes a radical mechanism and involves the formation of an iminyl radical, ring-opening of the cycloketone, insertion of SO2, addition of the sulfonyl radical to carbon-carbon triple bonds, ipso-cyclization and ester migration.

The visible-light-induced acylation/cyclization of alkynoates with acyl oximes for the construction of 3-acylcoumarins.

A nitrogen-centered radical-mediated carbon-carbon bond cleavage strategy is described to synthesize functionalized 3-acylcoumarins. The strategy is enabled by the visible-light-induced acylation/cyclization of alkynoates with various acyl oxime compounds in acetonitrile. The difunctionalization of carbon-carbon triple bonds precedes the generation of iminyl radicals, which is followed by the formation of acyl radicals. The acyl radicals then attack the carbon-carbon triple bonds, followed by 5-exo-trig cyclization and 1,2-ester migration. This strategy has wide substrate adaptability and good substituent tolerance.

Development of a Larval Zebrafish Model for Acute Organophosphorus Nerve Agent and Pesticide Exposure and Therapeutic Evaluation.

Organophosphorus compound exposure remains a present threat through agricultural accidents, warfare, or terrorist activity. The primary mechanism of organophosphorus toxicity is through inhibition of the enzyme acetylcholinesterase, with current emergency treatment including anticholinergics, benzodiazepines, and oxime reactivators. However, a need for more effective and broadly acting countermeasures remains. This study aimed to develop larval zebrafish as a high-throughput model for evaluating novel therapeutics against acute organophosphorus exposure. Larval zebrafish at six days post-fertilization were exposed to acute concentrations of seven organophosphorus compounds and treated with one of three oximes. Lethality studies indicated similar relative toxicity to that seen in the established rodent model, with chemical warfare agents proving more lethal than organophosphorus pesticides. Additionally, the organophosphorus-specific response for oxime reactivation of acetylcholinesterase was comparable to what has been previously reported. Behavioral studies measuring the visual motor response demonstrated greater efficacy for centrally acting oxime compounds than for those that are contained to the peripheral tissue. Overall, these results support the use of this larval zebrafish model as a high-throughput screening platform for evaluating novel treatments following acute organophosphorus exposure.

Bazı Oksim Bileşiklerinin Bağlanma Özelliklerinin Moleküler Kenetlenme Yöntemiyle İncelenmesi

Bu çalışmada, biyolojik aktivite gösterme potansiyeli yüksek olan bazı oksim bileşiklerinin, seçilmiş bazı proteinlerin aktif bölgesine bağlanma özellikleri moleküler kenetlenme (Doking) yöntemiyle incelenmiştir. Bu amaçla çalışılan tüm oksim ligand molekülleri, Yoğunluk Fonksiyonel Teorisi (DFT) yöntemiyle B3LYP fonksiyoneli ve 6-311G(d,p) temel seti kullanılarak Gaussian09 programında optimize edilmiştir. Optimize edilen tüm moleküllerin HOMO, LUMO ve HOMO-LUMO enerji farkları hesaplanmıştır. Çalışılan ligandlar için belirlenen kuantum kimyasal parametreleri ve inhibisyon aktiviteleri arasındaki ilişki de araştırılmıştır. Ligand moleküllerinin seçilen proteinlerle moleküler kenetlenme yöntemiyle bağlantı çalışmaları, ligandların optimize edilmiş geometrileri kullanılarak gerçekleştirilmiştir. Protein veri bankasından, seçilen proteinlerin kristal yapıları *.pdb formatında temin edilmiş ve bu kristal yapıların optimize ligandlarla etkileşimi SwissDock web sunucusu kullanılarak incelenmiştir. Moleküler kenetlenme çalışmaları sonucu, ligand-protein bağlanma enerjileri, ligand-protein arasında oluşabilecek hidrojen bağ bölgeleri ve sayısı tespit edilerek değerlendirilmiştir.

Synthesis and Properties of Moisture-Cured Reactive Polyurethane Containing Castor Oil and Oxime Compounds.

Reactive polyurethane hot-melt resin (moisture-cured reactive polyurethane, PUR) could successfully be prepared from poly(tetramethylene ether) glycol (PTMG), castor oil and dimethylglyoxime (DMG) by one or two-stage synthesis. Fourier-transform infrared spectroscopy (FTIR) analysis showed that the synthesis resins belonged to NCO-capped castor oil-based polyurethane. The thermal behaviors of the cured PUR were analyzed by differential scanning calorimeter (DSC) and dynamic mechanical analyzer (DMA) instruments. The results showed that the cured resin provided remeltable properties under the dosages of 3 wt% DMG. Furthermore, the phenomenon could be proved by FTIR analysis according to the characteristic absorption peak of NCO groups after the cured resin was heated. Comparing different syntheses, the resin prepared by one-stage synthesis showed random distribution of DMG with PUR structure and that prepared by two-stage synthesis had distribution of DMG with branching structure in the prepolymer. The former obtained lower remeltable temperatures from 90 to 130 °C than the latter temperatures, which had temperatures above 125 °C. The tensile test showed that all of the PUR films exhibited typical tough behavior. Thus, the cured resin with DMG dosages of 3 wt% provided remeltable and mechanical properties at the same time. Overall, the crosslinking density and numbers of dynamic bonds should be kept in balance for preparation of remeltable PUR.