Oxime Derivatives Research Articles

Synthesis of [13C₃]-B6 Vitamers Labelled at Three Consecutive Positions Starting from [13C₃]-Propionic Acid.

[13C3]-labelled vitamers (PN, PL and PM) of the B6 group were prepared starting from [13C3]-propionic acid. [13C3]-PN was synthesized in ten linear steps with an overall yield of 17%. Hereby, higher alkyl homologues of involved esters showed a positive impact on the reaction outcome of the intermediates in the chosen synthetic route. Oxidation of [13C3]-PN to [13C3]-PL was undertaken using potassium permanganate and methylamine followed by acid hydrolysis of the imine derivative. [13C3]-PM could be prepared from the oxime derivative of [13C3]-PN by hydrogenation with palladium.

Microwave-Assisted Synthesis and Characterization of Oxime Derivative of Substituted Chalcone and Its Nickel(II) Complex

In this study, microwave-assisted green synthesis of a complex of Ni (II)-2′,4′-dihydroxy 4-fluoro chalcone oxime has been carried out. The structure of the complex was characterized by elemental analysis, molar conductance, magnetic moment, IR, 1 H-NMR, 13 CNMR spectroscopic data and thermal studies. IR data showed that Ni(II) is coordinated to the ligand through the phenolic-O and azomethine-N of the latter. TGA studies confirmed the presence of coordinated water molecules. The 1 : 2 metal to ligands stoichiometry was indicated by mole ratio method, which was further confirmed by Job’s method of continuous variation modified by Turner and Anderson. Stability constant ( K s) of the complex determined by mole ratio method was 8.5245. Standard free energy change (Δ G 0 ) for metal–ligand complex formation was found to be –11.7026 K cal/mol at 27 ± 2°C. On the basis of analytical data, octahedral structure has been proposed for the complex. All compounds were tested for antibacterial activity and showed moderate to good activity against Escherichia coli and Staphylococcus aureus at different concentrations. In this study, we report synthesis of oxime derivative of chalcone and its Ni(II) complex in the hope of developing new compounds which might be used as analytical reagents or intermediates in the synthesis of various classes of bioactive compounds.

-Oxo anilides in Heterocyclic Synthesis: Novel Synthesis of Polyfunctionally Pyridines, Pyrimidines and Benzothiazole derivatives

Acetoacetanilide derivative 1 was reacted with aromatic aldehydes 2 to yield the arylidine derivatives 3 and 6a, b. The Hantzsch amides 7a,b were prepared by the one-pot cyclization reaction of a mixture of 2 moles of 1, aqueous ammonia and aromatic aldehydes. Treatment of 1 with ethanol containing equivalent amount of piperidine or morpholine furnished the isolable products 8a and 8b. Compound 1 underwent interamolecular heterocyclization on boiling conc. sulfuric acid, afforded 9. Also, the reaction of compound 1 with hydroxylamine hydrochloride in ethanol and sodium acetate afforded the oxime derivative 10. Furthermore, reactions of compound 1 with o-aminothiophenol furnished 11. Reactions of 1 with arylidine derivatives give compounds 13 and 16a-d. Treatment of compound 16d with elemental sulfur afforded the thieno[3,4-c]pyridine derivative 18. Treatment of 16a with hydrazine hydrate in boiling ethanol afforded the pyrazolo[3,4-b]pyridine derivatives 19. Also, compound 16a was reacted with ethylchloroacetate giving 20. Compound 20 was cyclized into the corresponding thieno[2,3-b]-pyridine derivative 21 upon boiling with ethanol containing a few drops of sodium ethoxide solution. Furthermore, compound 1 readily reacted with cyanothioacetamide to yield compound 22. Fusion of compound 1 with malononitrile over melting point without solvent in presence of ammonium acetate or refluxing in ethanolic piperidine afforded the pyridone 23a. Also, the pyridone derivative 23b was obtained by reacting compound 1 with cyanoacetamide. The reaction of acetoacetanilide 1 with -bromoacetophenones afforded 28a,b. Treatment of 1 with benzoyl and ethoxy carbonyl isothiocyanates afforded the pyrimidine derivatives 30a,b. The reaction of 1 with aminopyrazole gave the pyrazolopyrimidine 33. Coupling of 1 with diazonium salt of compounds 34a,b yielding 37a,b.

New glutathione conjugate of pyrrolizidine alkaloids produced by human cytosolic enzyme-dependent reactions in vitro.

The toxic metabolites of pyrrolizidine alkaloids (PAs) are initially formed by cytochrome P450-mediated oxidation reactions and primarily eliminated as glutathione (GSH) conjugates. Although the reaction between the reactive metabolites and GSH can occur spontaneously, the role of the cytosolic enzymes in the process has not been studied. The toxic metabolites of selected PAs (retrorsine, monocrotaline, senecionine, lasiocarpine, heliotrine or senkirkine) were generated by incubating them in 100mM phosphate buffer (pH7.4) containing liver microsomes of human, pig, rat or sheep, NADPH and reduced GSH in the absence or presence of human, pig, rat or sheep liver cytosolic fraction. The supernatants were analyzed using liquid chromatography connected to Finnigan LTQ ion-trap, Agilent QTOF or Thermo Scientific Q Exactive Focus quadrupole-orbitrap mass spectrometers. Retrorsine, senecionine and lasiocarpine yielded three GSH conjugates producing [M-H]- ions at m/z 439 (7-GSH-DHP (CHO)), m/z 441 (7-GSH-DHP (OH)) and m/z 730 (7,9-diGSH-DHP) in the presence of human liver cytosolic fraction. 7-GSH-DHP (CHO) was a novel metabolite. Monocrotaline, heliotrine and senkirkine did not produce this novel 7-GSH-DHP (CHO) conjugate. 7-GSH-DHP (CHO) disappeared when incubated with hydroxylamine, and a new oxime derivative was formed. This metabolite was formed only by the human liver cytosolic enzymes but not in the presence of rat or sheep liver cytosolic fractions under otherwise identical reaction conditions. 7-GSH-DHP (CHO) has not been reported before, and thus it was considered as a novel metabolite of PAs. This may clarify the mechanisms involved in PA detoxification and widely observed but less understood species differences in response to PA exposure.

Oximes of Nucleosides and Related Compounds: Synthesis, Reactions and Biological Activity

Background: Literature data on the synthesis and structure of oximes of nucleosides and related nitrogenous bases from pyrimidine and purine were reviewed. Synthesis of novel heterocyclic systems from nucleoside oximes related pyrimidine oximes was described. The biological activity of derivatives of nucleoside and nitrogenous base oximes was also reviewed. <p> Objective: The review focuses on the recent progress in the area of nucleoside oxime synthesis, reactions and biological activity. Conclusion: In summary, literature data on the synthesis and structure of oximes of nucleosides and related nitrogenous bases derived from pyrimidine, which play an important role in the biological processes, were reviewed. Synthesis of novel heterocyclic systems from nucleoside oximes related pyrimidine oximes was described. The biological activity of derivatives of nucleoside and nucleotide oximes was also reviewed. The studied class of compounds show a wide range of imino-amino and imino-nitroso tautomerism, which was investigated in the presented literature by 1H, 13C and 15N NMR spectroscopy methods. Also, according to the authors point of view, due to imino-amino and/or imino-nitroso tautomerism the nucleoside oximes show interesting activity. Most of the compounds exhibit biological activity characteristic of not only oxime derivatives, but also activity of hydroxylamines or nitroso compounds.

Oxime derivative unsymmetrical azine, its Ni(II), Cu(II) and Zn(II) complexes: Synthesis, spectroscopy and catecholase activity

Abstract1‐[(Z)‐{(2E)‐[(3E)‐3‐(hydroxyimino)butan‐lidene]hydrazinylidene}methyl]naphthalen ‐2‐ol, H2L (3) was synthesized by the agents of 2‐hydroxy‐1‐naphtaldehyde, 2,3‐butanedione monoxime and hydrazine in two steps. The structures of the compounds have been proposed by elemental analyses, spectroscopic data, that is, IR, 1H NMR, UV‐vis, X‐ray, mass spectra (ESI or TOF), molar conductivities and magnetic susceptibility measurements. The ligand has potentially three nitrogens and an oxygen donor to be able to bind a metal center. In the light of analytical and physical results, it was suggested that the ligand may coordinate to by N,O/N2/N2O donor set to form square planar, octahedral, distorted square planar and tetrahedral complexes. Proton NMR evidence indicating that the ligand coordinates the metal ion through the phenolic oxygen and nitrogen of imine in the nickel and zinc complexes. Molar conductivity measurements reveal that all the complexes are non‐electrolytes. In addition, catecholase activities of the complexes were studied. However, the only one of the complexes, 1b, behaves as an effective catalyst toward oxidation of 3,5‐di‐tert‐butylcatechol (3,5‐DTBC) to its corresponding quinone derivative in MeOH saturated with O2. The reaction follows Michaelis‐Menten enzymatic reaction kinetics with turnover numbers (kcat) 1.19 × 103/hour.

A Study of the Crystal Structure and Hydrogen Bonding of 3-Trifluoroacetyloxime Substituted 7-Acetamido-2-aryl-5-bromoindoles

The 7-acetyl-2-aryl-5-bromo-3-(trifluoroacetyl)indoles 1a-d were reacted with hydroxylamine hydrochloride (2.2 equiv.) in the presence of pyridine in ethanol under reflux to afford the corresponding diketo oxime derivatives 2a-d. Beckmann rearrangement of the latter with trifluoroacetic acid under reflux afforded the corresponding 7-acetamido-2-aryl-5-bromo-3-(trifluoroacetyloxime)indoles 3a-d. The structures of the prepared compounds were characterized using a combination of NMR (1H & 13C), IR, and mass spectrometric techniques. The molecular structure of the 3-trifluoroacetyloxime substituted 7-acetamido-2-aryl-5-bromoindoles was unambiguously confirmed by the single crystal X-ray diffraction data of 3d. Structural studies of 3d in the solid state by X-ray crystallography provided evidence of hydrogen bonding networks and π-stacking of the indole moiety. Compound 3d was crystallized in the trigonal space group R-3:H with unit cell dimensions a = 25.1614(13), b = 25.1614(13), c = 17.3032(9) Å, α = β = 90°, γ = 120°, V = 9486.9(11) Å3, Z = 6. The density functional theory (DFT) structural parameters (bond lengths, bond angles, and torsion angles) of the optimized geometry calculated using the B3LYP/6-311G basis set were found to compare favourably with those of the X-ray crystal structure.

Cytotoxicity of Synthesized 1,4-Naphthoquinone Oxime Derivatives on Selected Human Cancer Cell Lines.

In an effort to develop potent and selective antitumor agents, a series of 1,4-naphthoquinone oxime derivatives were designed and synthesized. The cytotoxicity of these compounds were evaluated against five human cancer cell lines (colorectal cancer cell: HCT-15, breast cancer cell: MDA-MB-231, liver cancer cell: BEL-7402, colorectal cancer cell: HCT-116 and ovarian cancer cell: A2780) in vitro. Among them, compound 14 was found to be the most potent cytotoxic compound against three cell lines (MDA-MB-231, BEL-7402 and A2780) with IC50 values of 0.66±0.05, 5.11±0.12 and 8.26±0.22 µM, respectively. Additionally, the length of the side chains and the position of the substituent may also affect the cytotoxic activity of the naphthoquinone oxime derivatives. In general, compound 14 effectively inhibited breast cancer cell proliferation and may become a promising anticancer agent.

Antibacterial and Antioxidant Screening of Semi-Synthetic Naringin Based Hydrazone and Oxime Derivatives

Background: The semi-synthesis of drugs from natural products is still limited and complicated. Recently, there has been compelling global need to develop novel and potential antibacterial and antioxidant agents. Objectives: The current study aimed at semi-synthesizing new derivatives from naringin, to verify their chemical structures and assess their antibacterial and antioxidant potentials. Methods: The semi-synthesis of naringin was conducted in the presence of hydrazone and oxime derivatives in acidic solution, while elemental and spectral analytical methods were used to verify the chemical structures of the semi-synthesized molecules. Also, to assess their antibacterial activity, the micro-broth dilution method with different American type culture collection (ATCC) strains as Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and clinical isolate methicillin-resistant Staphylococcus aureus (MRSA) were utilized. Moreover, 2, 2-Diphenyl-1-Picrylhydrazyl (DPPH) was used to assess the antioxidant activity of the derived compounds. Results: Three new hydrazone and oxime compounds were semi-synthesized from naringin and their chemical structures were identified by 13C NMR, IR, MS, and 1H NMR. Among the semi-synthesized compounds, the (2a) molecule showed the best antibacterial activity with a minimum inhibitory concentration (MIC) value of 62.5 μg/mL. Also, this compound exhibited the best antioxidant activity with IC50 3.7 μg/mL, in comparison with the other studied samples. Conclusions: Hydrazone (2a) compound could be used as a potent antioxidant and bacterial agent. Further studies are required to investigate other therapeutic effects of the (2a) molecule.

Synthesis and antiproliferative evaluation of oxime, methyloxime, and amide‐containing quinazolinones

Certain oxime, methyloxime, and amide‐containing quinazolinone derivatives were synthesized and evaluated in vitro for their antiproliferative activities against a panel of human cancer cell lines including nasopharyngeal carcinoma (NPC‐TW01), lung carcinoma (NCI‐H226), and leukemia (Jurkat). Quinazolinone 2 was inactive against all three cell lines tested, while quinazolinone 4 was weakly active against both Jurkat and H226 cancer cells with IC50 values of 6.55 and 12.27 μM, respectively, indicating that the oxime derivative 4 is more favorable than its ketone precursor 2. Our results have also indicated that quinazolinone 8g and its biphenyl counterpart 8f exhibited more potent antiproliferative activities than the positive control methotrexate against all three cancer cell lines tested. Among these quinazolinone derivatives, 8g was the most active against NPC‐TW01 with an IC50 value of 4.78 μM. Further study on NPC‐TW01 cell cycle distribution indicated that the compound 8g induced cell arrest at the G1/G0 phase in a time‐ and concentration‐dependent manner. Moreover, a characteristic hypo‐diploid DNA content peak (sub‐G1) was found to increase from 1 to 4% in NPC‐TW01 cells treated with 8g for 72 hr. These results indicate that 8g can induce cells arrest in the G1/G0 phase and cause cell death. Further structural optimization of 8g and detailed study of its antiproliferative mechanism are going on.

6-Substituted 1,4-Naphthoquinone Oxime Derivatives (III): Synthesis and Cytotoxic Evaluation

As a continuous study, a set of 23 new 6-substituted 1,4-naphthoquinone oxime derivatives are synthesized and screened for their in vitro cytotoxic activity. Four of those oxime derivatives demonstrate more potent cytotoxic activity towards K562, HCT-15, and HCT-116 cell lines than a reference drug 5-Fu. In particular, compound 21g exhibits the strongest inhibitory activity against K562 cell lines with IC50 values of 1.25 μM. According to flow cytometry data, compound 21g can arrest cell cycle at S phase and induce a strong apoptotic response in K562 cells. The preliminary structure-activity relationship study shows that the nature of substituents in positions 6 and 1' of 1,4-naphthoquinone derivatives significantly affect their cytotoxic activity.

Synthesis and Anticonvulsive Activity of 3- and 4-Benzoylpyridine Oxime Derivatives

We present here the synthesis of 3- and 4-benzoylpyridine oxime derivatives with potential anticonvulsant action. The most active compound in the maximum electric shock test was 4-benzoylpyridine O-2-morpholinoethyloxime oxalate (1a), i.p. doses of 60 – 150 mg/kg of which increased the survival of mice to 100%. The best effect in the corasol antagonism test was obtained with 4-benzoylpyridine O-(isonicotinoyl)oxime (2c), i.p. doses of 12.5 mg/kg of which increased the survival of mice to 67% and the latent period of onset of generalized tonic-clonic convulsions to 52 sec. Compound 1a had low toxicity (the i.p. LD50 in mice was 316 mg/kg) and a therapeutic index of 21.

Development of benzoxazole deoxybenzoin oxime and acyloxylamine derivatives targeting innate immune sensors and xanthine oxidase for treatment of gout

Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.

Синтез и противосудорожная активность производных оксимов 3- и 4-бензоилпиридинов

Представлен синтез производных оксимов 3- и 4-бензоилпиридинов с потенциальным противосудорожным действием. Наиболее активным соединением в тесте максимального электрошока оказался оксалат O-2-морфолиноэтилоксим 4-бензоилпиридина (1а), который в дозах от 60 до 150 мг/кг (внутрибрюшинно) увеличивал выживаемость мышей до 100 %. В тесте антагонизма с коразолом лучший эффект продемонстрировал O-(изоникотиноил)оксим 4-бензоилпиридина (2в), который в дозе 12,5 мг/кг (внутрибрюшинно) увеличивал выживаемость мышей до 67 % и латентное время наступления генерализованных тонико-клонических судорог на 52 с. Соединение 1а обладает низкой токсичностью (ЛД50 316 мг/кг, мыши, внутрибрюшинно) и терапевтическим индексом 21.

The semi-synthesis, biological evaluation and docking analysis of the oxime, hydrazine and hydrazide derivatives of platensimycin.

A dozen oxime, hydrazine and hydrazide derivatives of platensimycin (PTM) analogues were synthesized, some of which showed strong antibacterial activities and were shown to be stable under the bioassay conditions. Docking analysis revealed that they have certain new interactions with β-ketoacyl-[acyl carrier protein] synthase II (FabF), suggesting that Schiff base formation on its terpene scaffold is an effective strategy to diversify PTM structure.

Rhodium(iii)-catalyzed directed amidation of unactivated C(sp3)-H bonds to afford 1,2-amino alcohol derivatives.

A rhodium-catalyzed directed C(sp3)-H amidation to afford 1,2-amino alcohol oxime derivatives has been developed with good yields and a broad substrate scope. In previous methods for this type of reaction, 1-arylethan-1-ol oxime analogues were challenging substrates owing to strong competition from C(sp2)-H bond activation. This Rh-catalyzed C-H activation method overcomes the limitation of competitive C(sp2)-H bond activation.

Synthesis of gypsogenin derivatives with capabilities to arrest cell cycle and induce apoptosis in human cancer cells.

Thirty-two gypsogenin derivatives were synthesized and screened for their cytotoxic activities. Their structures were established using IR, 1H NMR, 13C NMR, and LC-MS spectroscopic data. In MTT assays nearly all the compounds displayed good cytotoxicity in the low μM range for several human tumour cell lines (A549, LOVO, SKOV3 and HepG2). Low IC50 values were obtained especially for the carboxamides 7a–7j, for an oxime derivative 3 and a (2,4-dinitrophenyl)hydrazono derivative 4. In particular, the IC50 values of compounds 4 (IC50 = 2.97 ± 1.13 µΜ) and 7 g (IC50 = 3.59 ± 2.04 µΜ) against LOVO cells were found to be much lower than those of the other derivatives and parent compound. These compounds were submitted to an extensive biological testing and proved compounds 4 and 7 g to act mainly by an arrest of the tumour cells in the S phase of the cell cycle. In addition, compounds 4 and 7 g triggered the apoptotic pathway in cancer cells, showing high apoptosis ratios.

Design, Synthesis, and Evaluation of GLUT Inhibitors.

The Warburg effect describes how most cancer cells exhibit higher-than-normal glucose consumption, not only under hypoxic conditions, but also when normal oxygen levels are present. Although glucose transporter 1 (GLUT1) has been found to play a key role in the cellular uptake of glucose, especially in cancer cells, where it is generally overexpressed, it has not been given consideration as a suitable target for the development of anticancer drugs. In this chapter, an example of molecular design and realization of novel GLUT1 inhibitors, including in silico modeling, chemical synthesis, and biological characterization, is provided. This process started with the identification of a focused series of oxime derivatives, originally designed as estrogen receptor (ER) ligands, which were structurally optimized in order to direct their activity towards GLUT1 and to minimize their binding to the ERs, leading to the production of efficient and selective inhibitors of glucose uptake in cancer cells.

Synthesis and Cytotoxicity of 6-Substituted 1,4-Naphthoquinone Oxime Derivatives (II)

In the present study, a series of 1,4-naphthoquinone oxime derivatives has been synthesized. The structures were confirmed by spectroscopic methods. The newly synthesized compounds were evaluated for their in vitro cytotoxicity. Among those, the compounds 8c, 8d, 8e, 12a, and 12b demonstrated potent cytotoxic activity comparable with that of the reference drug 5-Fu.

Semi-synthetic studies of α-onocerin derivatives for cytotoxicity

Up to 0.064% of α-onocerin (1) was isolated from Lycopodium clavatum. Twenty-one of its derivatives, 18 being new, were semi-synthesized through acylation, reduction, oxidation, and various other reactions. Their molecular structures were confirmed by means of NMR spectroscopy and mass spectrometry. The derivatives were evaluated for their inhibitory activities against acetylcholinesterase (AChE) and four cancer cell lines: HuCCA-1 (human cholangiocarcinoma), A-549 (lung carcinoma), HepG2 (hepatocarcinoma), and MOLT-3 (acute lymphoblastic leukemia). Introduction of a hydroxyl group at C-2/C-20 on α-onocerin (1) enhanced the cytotoxic activity. Most notably, the α-onocerin oxime derivative (22) selectively and significantly exerted cytotoxic activity against only the HepG2 cancer cell line.