Oxime Derivatives Research Articles

Recent Advances on Oximes Derivatives: Green Catalysis and Various Synthetic Routes

Nitrogen-containing acyclic, cyclic, and heterocyclic compounds and their derivatives have received increasing attention as a source of therapeutic agents. Oximes are an interesting class of Nitrogen-containing compounds possessing a wide variety of applications. Over the last decade, the interest in oximes and their derivatives has intensified. Many oxime derivatives using several preparation methods have been developed and evaluated for their biological activities. Due to their importance, oximes are subjected to many chemical transformations with the use of different chemicals to obtain numerous new derivatives. As a part of the continuing interest in oxime derivatives, we aim in this review to explore the green chemistry principles for the synthesis of oxime derivatives, as it offers promising pathways to more sustainable synthesis techniques that minimize waste and energy consumption and avoid hazardous methods. Additionally, it could inspire and stimulate researchers from various disciplines, such as chemists, biologists, and materials scientists to explore new applications for oximes derivatives.

Design, synthesis, and biological evaluation of imidazolylacetophenone oxime derivatives as novel brain-penetrant agents for Alzheimer's disease treatment

Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1−8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9−30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 μM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aβ42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.

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.

Inhibitory Effects and Mechanisms of the Novel Shikonin Derivative DMAKO-20 on Melanoma Metastasis and Invasion.

Cutaneous melanoma is a malignant tumor with an increasing incidence, prone to recurrence and metastasis. This study aims to explore the effects and mechanisms of the novel shikonin derivative 5,8-dimethyl alkannin oxime derivative (DMAKO-20) on the metastasis and invasion of melanoma cells. The inhibitory effects of DMAKO-20 on the melanoma cell line A375 were investigated through Cell Counting Kit-8 (CCK-8), Transwell and angiogenesis experiments. Network pharmacology and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to explore potential sites and pathways involved in this process. Additionally, quantitative polymerase chain reaction (qPCR) and Western blot experiments were conducted before and after drug treatment to verify the expression trends of related pathways and proteins. DMAKO-20 demonstrated selective inhibition of proliferation, invasion and migration of melanoma cells at low concentrations. The WNT pathway appears to be implicated in this process, as DMAKO-20 effectively attenuates its activation, consequently reducing matrix metalloproteinase 9 (MMP9) and Cellular Communication Network Factor 1 (CCN1)/cysteine-rich angiogenic inducer 61 (CYR61) levels. Such modulation inhibits melanoma dissemination and invasion into other tissues. DMAKO-20 exhibits the capability to suppress metastasis and invasion of melanoma cells, suggesting its potential for clinical application as an adjuvant therapy against melanoma.

Oxime chemistry in crop protection.

An overview is given on the significance of the oxime moiety in crop protection chemistry. This review focuses on the two most important aspects of agrochemical oximes, which are the occurrence and role of oxime groups in compounds with herbicidal, fungicidal and insecticidal activity, as well as the application of oxime derivatives as intermediates in the synthesis of crop protection agents not bearing any oxime function. Especially noteworthy is the fact, that in the synthesis of agrochemicals, oximes can be cyclized to isooxazoline, isoxazole, oxadiazole, oxazine, pyrrole, isothiazole and imidazole rings. © 2024 Society of Chemical Industry.

Synthesis and conformational aspects of 2-phenoxytetralones: Experimental verification and density functional theory (DFT) calculation

A series of 2-phenoxy-1-tetralones have been synthesized as conformationally constrained analogs of bioactive compounds 2-phenoxyacetophenones. A representative oxime derivative of 2-(3-methoxyphenoxy)-1-tetralone was selectively prepared and its (Z)-geometry was characterized by proton nuclear magnetic resonance (1H NMR) spectroscopy. Also, the conformational aspects of designed compounds were investigated by 1H NMR spectroscopy and density functional theory (DFT) calculations. The computational results showed that the more stable conformation in 5c is a conformer with equatorial orientation for 2-aryloxy group but the axial orientation in the related oxime 6 is predominated. Accordingly, it was demonstrated that the formation of (Z)-oxime on 1-position results in a remarkable conformational inversion on tetralin ring.

Eudistomins Y-Inspired Design and Divergent Optimization of Heteroaryl Ketones for New Antifungal Leads.

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 5a as a promising model, and the concomitant modification led to benzothiazolyl oxime 5am (EC50 = 5.17 μM) as a superior lead than fluoxastrobin (EC50 = 7.54 μM) against Sclerotinia sclerotiorum. Scaffold hopping of the phenyl subunit identified benzothiazolyl-pyridyl oxime as a novel antifungal scaffold accompanied by acquiring oxime 5bm with remarkable activity (EC50 = 3.57 μM) against Pyricularia oryzae. Molecular docking showed that candidate 5am 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 S. sclerotiorum. These results rationalize the discovery of antifungal candidates based on aryl heteroaryl ketone.

Thymoquinone oxime synthesis and its effects on melanoma cells: cytotoxic, genotoxic, and apoptotic evaluation

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 via fluorometry, mitochondrial membrane potential (MMP) was assessed using flow cytometry, glutathione (GSH) levels were measured using a luminometric GSH/oxidized glutathione assay, DNA damage via 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 (p < 0.001). In addition, MMP and GSH levels decreased significantly with increasing concentrations compared with the control (p < 0.001). Overall, these findings contribute to our understanding of the therapeutic potential of TQ and its derivatives in cancer treatment.

Safety assessment of the substance amines, di-C14-C20-alkyl, oxidised, from hydrogenated vegetable oil, for use in food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of amines, di-C14-C18-alkyl, oxidised, renamed by the Panel as amines, di-C14-C20-alkyl, oxidised, from hydrogenated vegetable oil. The substance amines, bis(hydrogenated tallow alkyl) oxidised, consisting of the same components, but originating from tallow, is currently authorised as FCM substance No 768. The vegetable-sourced substance is intended to be used at up to 0.1% w/w as antioxidant and/or stabiliser in the manufacture of polyolefin food contact materials (FCM) and articles intended for contact with dry, aqueous and acidic foods. The substance is a mixture consisting of linear N,N-dialkyl hydroxylamines and their corresponding amine, nitrone and oxime derivatives, as well as further components: tert-N-oxides, secondary amides and carboxylic acids. Specific migration was tested from polyethylene samples in 10% ethanol and 3% acetic acid for 2 h at 100°C followed by 10 days at 60°C. None of the non-authorised components were detected to migrate at detection limits (LoD) in the range 0.003-0.029 mg/kg. The LoD of authorised carboxylic acids was 0.35 mg/kg. The Panel reassessed the genotoxicity studies carried out on FCM No 768 and evaluated two new bacterial reverse mutation tests on the nitrone and oxime derivatives as well as new (qualitative/quantitative) structure-activity relationship (Q)SAR analyses on other components. The Panel concluded that the substance did not raise a concern for genotoxicity. The Panel concluded that the substance is not of safety concern for the consumers if it is used as an additive at 0.1% w/w in the manufacture of polyolefin FCM intended to be in contact with foods simulated by food simulants A, B, C and E, except for infant formula and human milk, for storage above 6 months at room temperature and below, including hot-fill conditions and heating up to 100°C for 2 h.

Preparation and bioevaluation of a novel 99mTc-labelled propylene amine oxime (PnAO) containing two 4-methyl-2-nitroimidazole groups as a promising tumor hypoxia imaging agent

Hypoxia is a common phenomenon in solid tumors, and its presence inhibits the efficacy of tumor chemotherapy and radiotherapy. Accurate measurement of hypoxia before tumor treatment is essential. Three propylene amine oxime (PnAO) derivatives with different substituents attached to 2-nitroimidazole were synthesized in the work, they are 3,3,9,9-tetramethyl-1,11-bis(4-bromo-2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioxime (Br2P2), 3,3,9,9-tetramethyl-1,11-bis(4-methyl-2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioxime (Me2P2) and 3,3,9,9-tetramethyl-1,11-bis(4,5-dimethyl-2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioxime (2Me2P2). The three compounds were radiolabeled with 99mTc to give three complexes([99mTc]Tc-Br2P2, [99mTc]Tc-Me2P2 and [99mTc]Tc-2Me2P2) with good in vitro stability. [99mTc]Tc-Me2P2 with a more suitable reduction potential had the highest hypoxic cellular uptake, compared with [99mTc]Tc-2P2 that have been previously reported, [99mTc]Tc-Br2P2 and [99mTc]Tc-2Me2P2. Biodistribution results in S180 tumor-bearing mice demonstrated that [99mTc]Tc-Me2P2 had the highest tumor-to-muscle (T/M) ratio (12.37 ± 1.16) at 2 h in the four complexes. Autoradiography and immunohistochemical staining results revealed that [99mTc]Tc-Me2P2 specifically targeted tumor hypoxic regions. The SPECT/CT imaging results showed that [99mTc]Tc-Me2P2 could target the tumor site. [99mTc]Tc-Me2P2 may become a potential hypoxia imaging agent.

Synthesis and Characterization of Oxime Derivatives and their Some Transition Metal Complexes with Thiadiazole Groups: Biological Activities, and Molecular Docking Studies of the Ligands

AbstractThis study involved the synthesis and investigation of the anticancer and antioxidant capabilities of six newly developed ligands generated from 1,3,4‐thiadiazole and diphenyl ether keto oxime which has never been synthesized before, together with their transition metal complexes. The obtained ligands were characterized using elemental analysis, FTIR, 1H NMR, 13C NMR, and mass spectroscopy. Polymeric complexes of the obtained ligands were synthesized by reacting all ligands with MCl2.nH2O (M: Mn2+/Co2+)/Ni2+/Cu2+)) salts. The polymeric complexes′ structures were determined using elemental analysis, ICP‐AES, FTIR spectroscopy, UV‐vis spectroscopy, magnetic susceptibility analysis, and thermogravimetric analysis. Subsequently, the ligands were examined for their anticancer properties. To achieve this objective, the HT‐22 cell line, which consists of healthy mouse hippocampus neuronal cells, is utilized as the control group. Additionally, the MCF7 (breast cancer), MDA‐MB‐231 (breast cancer), C6 (rat glioma), HT‐29 (colon cancer), and A549 (lung carcinoma) cell lines are employed in cell culture research as representatives of cancerous cell lines. Based on the cell culture investigations, some of the synthesized ligands showed moderate to good anti‐cancer activity, especially for both colon cancer and brain tumors. Finally, a molecular docking analysis was conducted utilizing MOE software to ascertain the binding affinity between the synthesized ligands and the specific proteins of interest.

Mechanistic insight into the synergistic role of the dual-surfactant system as a green solvent for deoximation reaction: An experimental and computational analysis

Deoximation reaction is one of the most essential transformations in organic synthesis for the precise chemical manufacturing of carbonyl compounds. Developing catalytic deoximation techniques is highly demanding for environmental protection and minimizing expenses in fine chemical operations. Herein, we have reported an environmentally friendly, low-cost, and sustainable approach for regenerating carbonyl compounds from numerous oxime derivatives using microwave irradiation. The method uses I2 and an aqueous solution ofAcacia auriculiformis as the green solvent. The concentration ofAcacia auriculiformiswas discovered to correlate with the percentage production of carbonyl compounds. However, using the dual-surfactant system deliberately improved the regeneration of carbonyl compounds with up to 82% yield at 60:40 ratio. With DFT analysis and quantum chemical parameters, the chemical reactivity and electronic properties of the surfactant systems were determined. Also, the mechanistic interpretation of the actual reaction in the micellar core is depicted, which is well supported by the computational analysis. Overall, our method is green, low-cost, energy-saving, and avoids using toxic reagents and solvents.

Synthesis, Spectral Analysis, DFT and Molecular docking studies of Some Novel Oxime Derivatives

A series of novel Di‑tert‑butyl(E)-4‑hydroxy-6-(hydroxyimino)-4-methyl-2-arylcyclohexane-1,3-dicarboxylate derivatives were synthesized in two steps with excellent yields. In the First step, tert‑butylacetoacetate and substituted benzaldehyde were directly condensed using methylamine catalyst in ethanol as a solvent to create substituted 1,3-bis(tert‑butoxycarbonyl)-cyclohexanone. A second stage involved synthesizing BHMAC (Ar = pH and Ar = p-OCH3C6H4) by treating the respective ketones in an ethanol medium with hydroxylamine hydrochloride and sodium acetate trihydrate. NMR, IR, and mass spectroscopy were used to confirm the oxime derivatives. Density functional theory calculations at the DFT/B3LYP level using 6–31G++ (d, p) have been performed to reproduce the structure and geometry in order to understand the electrical behavior of synthesized compounds. Using bovine serum albumin, a protein denaturation test is used to assess anti-inflammatory efficacy. BHMAC demonstrates conventional pharmacological molecules in its notable anti-inflammatory action and has effects that are dependent on concentration. Utilizing the phosphomolybdenum technique, the total antioxidant activity of the 2,4-bis(tert‑butoxycarbonyl)-cyclohexanone oxime (2 a and 2 b) was assessed standard Vitamin C medications .The results revealed that 2 a & 2 b possess significant antioxidant activity Molecular docking experiments indicate that the chemical may interact with anti-inflammatory and antioxidant causing enzymes. Strong binding energies and inhibition constants with cyclooxygenase (PDB: 1PGG) are demonstrated by BHMAC, suggesting that it is a suitable material for investigations pertaining to anti-inflammatory. BHMAC's remarkable anti-inflammatory and antioxidant properties, together with its synthesis and characterization, highlight its potential as a viable candidate for more biomedical research and therapeutic development.

Chemical Fingerprinting of Biomass Burning Organic Aerosols from Sugar Cane Combustion: Complementary Findings from Field and Laboratory Studies.

Agricultural fires are a major source of biomass-burning organic aerosols (BBOAs) with impacts on health, the environment, and climate. In this study, globally relevant BBOA emissions from the combustion of sugar cane in both field and laboratory experiments were analyzed using comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. The derived chemical fingerprints of fresh emissions were evaluated using targeted and nontargeted evaluation approaches. The open-field sugar cane burning experiments revealed the high chemical complexity of combustion emissions, including compounds derived from the pyrolysis of (hemi)cellulose, lignin, and further biomass, such as pyridine and oxime derivatives, methoxyphenols, and methoxybenzenes, as well as triterpenoids. In comparison, laboratory experiments could only partially model the complexity of real combustion events. Our results showed high variability between the conducted field and laboratory experiments, which we, among others, discuss in terms of differences in combustion conditions, fuel composition, and atmospheric processing. We conclude that both field and laboratory studies have their merits and should be applied complementarily. While field studies under real-world conditions are essential to assess the general impact on air quality, climate, and environment, laboratory studies are better suited to investigate specific emissions of different biomass types under controlled conditions.

Design, Synthesis and Anticancer Activity of Novel Substituted (E)-2-Morpholinoquinoline- 3-carbaldehyde-O-((-1-aryl-1H-1,2,3-triazol-4-yl)methyl)oxime Derivatives

A new series of substituted (E)-2-morpholinoquinoline-3-carbaldehyde-O-((-1-phenyl-1H-1,2,3-triazol-4-yl)methyl)oxime scaffolds were synthesized from involving alkynyl quinoline oximes with various aryl azides by click reaction obtained corresponding compounds with high yields. The synthesized compounds were characterized by using IR, 1H NMR, 13C NMR and HRMS data. All the synthesized compounds screened anticancer activity against MCF-7, HeLa, PC-3 cell lines. All the compounds exhibited good results among them 8b, 8g and 8i compounds have shown prominent anticancer activity are compared to standard drug doxorubicin.

Acute toxicity study of a new dibenzofuran oxime derivative GIZH-272 in mice

Relevance. Acute toxicity testing is a common procedure for preclinical safety testing of potential agents. The purpose of this study was to study the acute toxicity of the compound GIZH-272, a new dibenzofuran oxime derivative with anti-ischemic and anticonvulsant effects. Methods. The compound was administered to mice intraperitoneally and orally once. Within 14 days, the condition of the animals was monitored, clinical manifestations of intoxication were recorded, and changes in the dynamics of body weight and its growth were recorded. Results. It was found that the test compound at maximum doses did not lead to the death of mice. Therefore, the data obtained according to the classification of Sidorov K.K. (1973), make it possible to attribute GIZH-272 to the 5th class of toxicity — "practically non-toxic substance". In accordance with GOST 12.1.007-76, the GIZH-272 compound belongs to the 4th hazard class (low-hazard substance) for oral administration.

Oxime derivatives of betulonic acid and platanic acid as novel cytotoxic or antiviral agents

Less frequently studied plant triterpenoids betulonic acid and platanic acid were selected to design, synthesize and investigate their oxime derivatives as novel and potentially effective cytotoxic and/or antiviral agents.

A review on oxime functionality: an ordinary functional group with significant impacts in supramolecular chemistry.

The oxime functional group is pivotal in chemistry, finding extensive applications in medical science, catalysis, organic functional group transformations, and the recognition of essential and toxic analytes. While the coordination chemistry of oxime derivatives has been thoroughly explored and several reviews have been published on this topic in reputable journals, a comprehensive review encompassing various aspects such as crystal engineering, cation and anion recognition, as well as coordination chemistry activities, is still in demand. This feature article highlights the diverse applications of oxime derivatives across multiple domains of chemistry, including medicine, agriculture, crystal engineering, coordination chemistry, and molecular recognition studies. Each of the oxime derivatives in this feature article are meticulously described in terms of their medicinal applications, crop protection, crystal engineering attributes, analyte recognition capabilities, and coordination chemistry aspects. By providing a comprehensive overview of their versatile applications, this article aims to inspire researchers to explore and develop novel oxime-based derivatives for future applications.

New 1,2,3-triazoles and their oxime derivatives: AChE/BChE enzyme inhibitory and DNA binding properties

1,2,3-Triazole compounds (1a–3a) and their oxime derivatives (1b–3b) were synthesized. The structures of these synthesized compounds were characterized using common spectroscopic methods. Crystal structures of the compounds 3, 2b and 3b were determined by single crystal X-ray diffraction studies. The acetylcholinesteras (AChE) and butyrylcholinesterase (BChE) cholinesterase inhibitor (ChEI) and DNA/calf serum albumin (BSA) binding properties of the compounds were examined. DNA binding studies have shown that compounds interact with DNA through 1,2,3-triazole and oxime groups. When the binding constant K b values were compared, it was revealed that compound 3b (K b = 4.6 × 105 M−1) with oxime in its structure binds more strongly than the others. In addition, in vitro BSA binding studies showed that compounds 1b and 3b exhibited higher binding affinity. These results confirm that the quenching is due to the formation of a compound resulting from the static quenching mechanism, rather than being initiated by a dynamic mechanism. Likewise, when the enzyme activity of the compounds was examined, the compounds exhibited high inhibitory activity against AChE. The highest activity was observed for compounds 2b and 3b (8.6 ± 0.05 and 4.8 ± 0.052 µM). It was observed that the compounds were not selective with respect to BChE. Communicated by Ramaswamy H. Sarma

Exploring the Catalytic Efficiency of Copper-Doped Magnetic Carbon Aerogel for the Coupling Reaction of Isatin Oxime with Phenylboronic Acid Derivatives

AbstractA highly efficient catalyst, Cu-doped poly(N-[3-(dimethylamino)propyl]methacrylamide, acrylic acid, N-vinyl imidazole) (PDAI) magnetic carbon aerogel (CPIMCA), was successfully employed for the synthesis of isatin nitrone derivatives. The 3D porous CPIMCA catalyst demonstrated outstanding performance through the application of a coupling reaction between isatin oxime and phenylboronic acid derivatives, providing up to 98% yield of the required nitrone derivatives. Remarkably, the incorporation of copper within the polymeric structure of the magnetic carbon aerogel exhibited a significant influence on catalytic activity, even at a low overall copper content of approximately 2%. This was confirmed through EDX elemental mapping analysis, further establishing the competence of the catalyst for catalytic reactions. Comparative studies revealed that CPIMCA outperformed Cu(Oac)2 catalyst, providing a notable 10–15% increase in product yield. This superior performance can be attributed to the unique synergistic effect of copper, iron, and carbon aerogel as the polymeric matrix, highlighting the exceptional capabilities of CPIMCA as a catalyst.