Oxime Derivatives Research Articles

QSAR models for the reactivation of sarin inhibited acetylcholinesterase by quaternary pyridinium oximes based on Monte Carlo method.

Monte Carlo method has been used as a computational tool for building QSAR models for the reactivation of sarin inhibited acetylcholinesterase (AChE) by quaternary pyridinium oximes. Simplified molecular input line entry system (SMILES) together with hydrogen-suppressed graph (HSG) was used to represent molecular structure. Total number of considered oximes was 46 and activity was defined as logarithm of the AChE reactivation percentage by oximes with concentration of 0.001 M. One-variable models have been calculated with CORAL software for one data split into training, calibration and test set. Computational experiments indicated that this approach can satisfactorily predict the desired endpoint. Best QSAR model had the following statistical parameters: for training set r2=0.7096, s=0.177, MAE=0.148; calibration set: r2=0.6759, s=0.330, MAE=0.271 and test set: r2=0.8620, s=0.182, MAE=0.150. Structural indicators (SMILES based molecular fragments) for the increase and the decrease of the stated activity are defined. Using defined structural alerts computer aided design of new oxime derivatives with desired activity is presented.

Recent advances of chroman-4-one derivatives: Synthetic approaches and bioactivities

Chroman-4-one scaffold is a privileged structure in heterocyclic chemistry and drug discovery. Also, chroman-4-ones are important intermediates and interesting building blocks in organic synthesis and drug design. The structural diversity found in the chroman-4-one family led to their division into several categories including benzylidene-4-chromanones, flavanones (2-phenyl-4-chromanones), isoflavanones (3-phenyl-4-chromanones), spirochromanones, and C-4 modified chroman-4-ones such as hydrazones and oxime derivatives. This review addresses the most significant synthetic methods reported on 4-chromanone-derived compounds and consequently emphasizes on the biological relevance of such compounds.

ChemInform Abstract: The Diels—Alder Reactions of para‐Benzoquinone Nitrogen‐Derivatives: An Experimental and Theoretical Study.

AbstractThe most reactive dienophile is the N‐tosyl derivative, followed by p‐benzoquinone, N‐tosyl‐oxime, and the oxime derivative which does not react in this reaction.

RAHB concept and σ-skeleton in some oximes of 3-hydroxy fulvene; DFT, AIM, ELF and NBO studies

The resonance-assisted hydrogen bond (RAHB) concept and influence of σ-skeleton of the molecule on the intramolecular hydrogen bonds (IHB) of some substituted oxime derivatives of 3-hydroxy fulvene have been evaluated by use of atoms in molecules, electron localization function and natural bond orbital and geometrical analyses. The results, based on some aromaticity indicators (HOMA, pEDA and PDI), indicate that aromaticity and electron delocalization in the IHB quasi-ring of 3-hydroxyfulvene-2-aldoxime derivatives increase by increasing the electron-donating character of substituents. Contrary to the expectations from RAHB concept, the results show that the strength of IHB decreases with increasing the π-electron delocalization in the quasi-ring of the target fulvene derivatives. Accordingly, the RAHB concept could not describe the trend of the IHB strength in these compounds. Instead, a good correlation between the strength of IHB and the σ-skeleton of the studied molecules has been presented, which keeps the HB donor and acceptor coplanar, more linear, and closer to each other to make IHB stronger.

Synthesis and Bioactivities of Novel Pyrazole Oximes Containing Substituted Thiadiazole Moiety

In order to find novel potent pesticide from pyrazole oxime derivatives, a series of new pyrazole oximes carrying substituted thiadiazole moiety were prepared by the introduction of the key thiadiazole backbone into the molecules of pyra- zole oximes. The structures of the title compounds were characterized by 1 H NMR, 13 C NMR and elemental analysis. Prelimi-

β-Oxo Anilides in Heterocyclic Synthesis: Novel Synthesis of Substituted Pyridazinones, Pyridine, Pyrimidines and Pyrazolotriazines

Diazotization and coupling of acetoacetanilide derivative 1 with aromatic amines afforded the arylhydrazones 2a,b. Arylhydrazones 2a,b were treated with (DMF-DMA) to yield the pyridazine derivatives 3a,b in good yield. Pyridazinone was treated with hydrazine hydrate to yield 4a,b. Reaction of 2a with hydroxylamine hydrochloride afforded the oxime derivative 5. Similarly, the reaction of acetoacetanilide 1 with hydroxylamine hydrochloride gave 3-hydroxyimino-N-p-tolyl-butyramide 8 not the pyrazolone 9. The reaction of anilide 4 with aromatic aldehydes yielded 10a,b. Also, when anilide 4 was reacted with a mixture of aromatic aldehydes, urea or thiourea afforded the pyrimidines 11a,b. The reaction of anilide 1 with active methylene reagents was also investigated. So, 1 was reacted with malononitrile to give the pyridone derivative 12. Similarly, anilide 1 was reacted with cyanoacetamide under the same reaction conditions to yield 4-methyl-2-oxo-6-p-tolylamino-1,2-dihydro-pyridine-3-carbonitrile 13 in quantitative yield. The reaction of 1 with ylidenemalononitrile depends on structure of substituent. Thus, reaction of 1 with benzylidenemalononitrile or naphthylidenemalononitrile afforded 14a,b, while that with p-anisidine-malononitrile afforded 15. Coupling 1 with diazotized 16 - 18 afforded 19 - 21 respectively. Condensing 1 and aminopyrazoles 22a,b afforded the acyclic adduct 23a,b rather than the pyrazolopyrimidine 24a,b.

Microwave-assisted synthesis, molecular docking and antiproliferative activity of (3/5-aryl-1,2,4-oxadiazole-5/3-yl)(3,4,5-trimethoxyphenyl)methanone oxime derivatives

A microwave-assisted synthesis method of building a 1,2,4-oxadiazole skeleton was developed.

Synthesis, characterization, computational calculation and biological studies of some 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oxime derivatives

A new series of 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes (17–24) were designed and synthesized from 2,6-diarylpiperidin-4-one oximes (9–16) with propargyl bromide. Unambiguous structural elucidation has been carried out by investigating IR, NMR (1H, 13C, 1H−1H COSY and HSQC), mass spectral techniques and theoretical (DFT) calculations. Further, crystal structure of compound 17 was evaluated by single crystal X-ray diffraction analysis. Single crystal X-ray structural analysis of compound 17 evidenced that the configuration about CN double bond is syn to C-5 carbon (E-form). The existence of chair conformation was further confirmed by theoretical DFT calculation. All the synthesized compounds were screened for in vitro antimicrobial activity against a panel of selected bacterial and fungal strains using Ciprofloxacin and Ketoconazole as standards. The minimum inhibition concentration (MIC) results revealed that most of the 2,6-diaryl-1-(prop-2-yn-1-yl)piperidin-4-one oximes (17, 19, 20 and 23) exhibited better activity against the selected bacterial and fungal strains.

ChemInform Abstract: Synthesis, Reactions and Biological Activity of Derivatives of Oximes of Four‐Membered Heterocycles

AbstractReview: 129 refs.

Synthesis and fungistatic activity of aryl aldoxime derivatives

The antifungal activity of 13 arylaldoxime ester and ether derivatives was tested against 4 dermatophytes Trichophyton mentagrophytes (TM), Microsporum canis (MC); M.cookei, and M.gypseum. Structures of all new compounds prepared from aryl aldehydes were established by spectral means. The tests were performed on the Sabouraud Dextrose Agar (SDA) substrate. The sensitivity of the dermatophyte strains towards oxime derivatives was established by determining MIC and MFC values. The tested compounds showed a moderate fungicidal activity reaching 100% inhibition rate at 1% concentration. The activity against M.canis of 4 derivatives was higher than the activity of a reference drug clotrimazole. A novel group of biologically active compounds was introduced. Simple aldoxime derivatives can be developed into a new class of antifungals.

Synthesis and insecticidal activity of new oxime derivatives of podophyllotoxin-based phenazines against Mythimna separata Walker

To discover new natural-product-based insecticidal agents, a series of novel oxime derivatives of podophyllotoxin-based phenazines modified in the C, D and E rings of podophyllotoxin were prepared and tested as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. The steric configuration of IIIc was unambiguously confirmed by single-crystal X-ray diffraction analysis. Compounds IIIa–d, and IIIi exhibited an equal or higher insecticidal activity than toosendanin.

In vitro Reactivation of Chlorpyrifos-inhibited Rat Brain Acetylcholinesterase from 2-Quinolone Substituted Thiazole derivatives

Organophosphate (OP) compounds exert inhibition of acetylcholinesterase (AChE) by irreversibly binding to catalytic site of an enzyme. Despite continued efforts to discover improved reactivators, there has been little success towards innovation of AChE reactivators. In the present investigation, new series of 2-quinolone fused thiazole derivatives 3a-3f and 4a-4f were evaluated for their in vitro reactivation efficacy against chlorpyrifos inhibited AChE using 2-PAM as standard. Even though the non oxime derivatives were not as effective as pralidoxime (2-PAM), but exhibited considerable AChE reactivation. The compounds, 3b, 3c, 3f, and 4f, showed promising reactivation against chlorpyrifos inhibited AChE.

Synthesis and evaluation of novel alkannin and shikonin oxime derivatives as potent antitumor agents

A set of forty alkannin and shikonin oxime derivatives were firstly designed and synthesized. Their cytotoxicities against three kinds of tumor cells and a normal cell line were tested and compared with alkannin and shikonin. The cell-based investigation demonstrated that some oxime derivatives were more or comparatively effective to the lead compounds, especially their selective and excellent antitumor activities towards K562 cells with no toxicity in normal cells. We may conclude that oximate modification to the mother nucleus of alkannin and shikonin is an available approach to acquire potent antitumor agents.

Recent Advances in the Synthesis of Heterocycles from Oximes

This review demonstrates that oximes and their derivatives are valuable starting materials for the preparation of many classes of heterocyclic compounds. The main group of reactions includes the cyclization of unsaturated oxime derivatives. Using these starting materials pyrroles, isoxazoles, pyridines and isoquinolines were prepared. Some heterocyclic systems (for example, seven-membered rings) were obtained using the classical Beckmann rearrangement and novel reagents and conditions.

A steroidal Na+/K+ ATPase inhibitor triggers pro-apoptotic signaling and induces apoptosis in prostate and lung tumor cells.

Recently we have reported potent anti-cancer actions of various steroidal Na(+)/K(+) ATPase inhibitors in multiple cell lines. Furthermore, the most powerful compound identified in this study, the 3-[(R)-3-pyrrolidinyl]oxime derivative (3-R-POD), was highly effective in various tumor cell lines in vitro, and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. In the present study we have addressed the molecular mechanisms implicated in the anti-cancer actions of 3-R-POD. We report here that 3-R-POD induces strong apoptotic responses in A549 lung- and in DU145 prostate- cancer cells. These effects are accompanied by significant upregulation of caspase-3 activity. Focussing on A549 cells, we further demonstrate late downregulation of BCL-2- and upregulation of c-Fos- gene transcription. In addition, the steroidal Na(+)/K(+) ATPase inhibitor induced late de-phosphorylation of Focal Adhesion Kinase (FAK) and activation of p38 MAPK. Our findings suggest that the steroidal Na(+)/K(+) ATPase inhibitor 3-R-POD induces apoptosis, paralleled by altered BCL-2 and c-Fos gene transcription, inhibition of the pro-survival FAK signalling, up-regulation of the pro-apoptotic p38 MAPK pathway and stimulation of caspase-3 activity.

An efficient synthesis of pyridoxal oxime derivatives under microwave irradiation.

Quaternary salts of pyridoxal oxime have been synthesized by the quaternization of pyridoxal oxime with substituted phenacyl bromides using microwave heating. Microwave-assisted rapid synthesis was done both in solvent (acetone) and under solvent-free conditions. Good to excellent yields (58%–94%) were obtained in acetone in very short reaction times (3–5 min) as well as in the solvent-free procedure (42%–78%) in very short reaction times (7–10 min) too. Effective metodologies for the preparation of pyridoxal oxime quaternary salts, having the advantagies of being eco-friendly, easy to handle, and performed in shorter reactions time are presented. The structure of compound 7, in which a 4-fluorophenacyl moiety is bonded to the pyridinium ring nitrogen atom, was unequivocally confirmed by the single-crystal X-ray diffraction method.

Steroidal Cardiac Na<sup>+</sup>/K<sup>+</sup> ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo

Sodium potassium pump (Na(+)/K(+)ATPase) is a validated pharmacological target for the treatment of congestive heart failure. Recent data with inotropic drugs such as digoxin & digitoxin (digitalis) suggest a potent anti-cancer action of these drugs and promote Na(+)/K(+)ATPase as a novel therapeutic target in cancer. However, digitalis have narrow therapeutic indices, are pro-arrhythmic and are considered non-developable drugs by the pharmaceutical industry. On the contrary, a series of recently-developed steroidal inhibitors showed better pharmacological properties and clinical activities in cardiac patients. Their anti-cancer activity however, remained unknown. In this study, we synthesized seventeen steroidal cardiac inhibitors and explored for the first time their anti-cancer activity in vitro and in vivo. Our results indicate potent anti-cancer actions of steroidal cardiac inhibitors in multiple cell lines from different tumor panels including multi-drug resistant cells. Furthermore, the most potent compound identified in our studies, the 3-[(R)-3- pyrrolidinyl]oxime derivative 3, showed outstanding potencies (as measured by GI50, TGI and LC50 values) in most cells in vitro, was selectively cytotoxic in cancer versus normal cells showing a therapeutic index of 31.7 and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. Collectively, our results suggest that previously described cardiac Na(+)/K(+)ATPase inhibitors have potent anti-cancer actions and may thus constitute strong re-purposing candidates for further cancer drug development.

NO-donating oximes relax corpora cavernosa through mechanisms other than those involved in arterial relaxation.

Erectile dysfunction (ED), as well as many cardiovascular diseases, is associated with impaired nitric oxide (NO) bioavailability. Recently, oxime derivatives have emerged as vasodilators due to their NO-donating capacities. However, whether these oximes offer therapeutic perspectives as an alternative NO delivery strategy for the treatment of ED is unexplored. This study aims to analyze the influence of formaldoxime (FAL), formamidoxime (FAM), and cinnamaldoxime (CAOx) on corporal tension and to elucidate the underlying molecular mechanisms. Organ bath studies were carried out measuring isometric tension on isolated mice corpora cavernosa (CC), thoracic aorta, and femoral artery. After contraction with norepinephrine (NOR), cumulative concentration-response curves of FAL, FAM, and CAOx (100 nmol/L-1 mmol/L) were performed. FAL-/FAM-induced relaxations were evaluated in the absence/presence of various inhibitors of different molecular pathways. FAL, FAM, and CAOx relax isolated CC as well as aorta and femoral artery from mice. ODQ (soluble guanylyl cyclase-inhibitor), diphenyliodonium chloride (nonselective flavoprotein inhibitor), and 7-ethoxyresorufin (inhibitor of CYP450 1A1 and NADPH-dependent reductases) substantially blocked the FAL-/FAM-induced relaxation in the arteries but not in CC. Only a small inhibition of the FAM response in CC was observed with ODQ. This study shows for the first time that NO-donating oximes relax mice CC. Therefore, oximes are a new group of molecules with potential for the treatment of ED. However, the underlying mechanism(s) of the FAL-/FAM-induced corporal relaxation clearly differ(s) from the one(s) involved in arterial vasorelaxation.

English

A series of new 2,4-difluorophenyl(piperidin-4-yl)methanone oxime derivatives 4a-h and 5a-e were synthesized by the reaction of 2,4-difluorophenyl(piperidin-4-yl)methanone oxime with various sulfonyl and acid chlorides. The synthesized compounds were characterized by elemental analyses, FT- IR, 1 H NMR and LCMS spectral studies. All compounds were evaluated for in vitro antibacterial and antifungal activities. Compounds 4b, 4g and 5e exhibited good antimicrobial activity against tested pathogenic bacterial and fungal strains. Compound 4b would be a more activity deserves further research.

Synthesis and structure–activity relationship of cyclopentenone oximes as novel inhibitors of the production of tumor necrosis factor-α

3-Alkyl-2-aryl-2-cyclopenten-1-one oxime derivatives (1) were studied as a novel class of inhibitors of tumor necrosis factor α (TNF-α) with regard to synthesis and in vitro SAR inhibition of TNF-α. The in vitro IC50 values of these compounds in rat and human peripheral blood mononuclear cells were at the sub-micromolar level.