Potential cytostatic agents: delta-2, alpha-chroman-malononitriles.
Explore the source record for details and available documents.
Antineoplastic Agents↗
SEARCH · Search PubMed
Results for “MALONONITRILE”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Effect of O-chlorobenzylidene malononitrile (CS) on tissue glycolysis & oxidation.
Explore the source record for details and available documents.
Animals↗
The effect of O-chlorobenzylidine malononitrile on spermatogenesis in the rat.
Explore the source record for details and available documents.
Animals↗
The effect of o-chlorobenzylidene malononitrile (tear gas) on the polymerase chain reaction.
Explore the source record for details and available documents.
DNA, Viral↗
Heterocyclic synthesis with nitriles: new routes for synthesis of pyridazines, pyridines and their fused derivatives.
Phenylazocyanothioacetamide 1 reacts with malononitrile to afford the pyridinethione 4 which reacts with phenacylbromide to yield the pyridine-S-phenacyl derivative 6. 1 reacts with ethyl cyanoacetate to yield the pyridazine derivative, 8, and with phenacyl bromide to afford the N-phenacyl derivative 11, instead of the thiazole 10. Compound 11 afforded the pyrazolopyridine 13 on reaction with malononitrile while 10 was obtained on coupling of the thiazole 14 with diazotised aniline. Compound 10 reacts with malononitrile to afford the thiazolyl pyridazine 15. Compound 1 reacts with malononitrile dimer to afford the pyridopyridazine derivative 17a. 1 reacts also with active methylene heterocycles to afford the pyrazolo and thiazolo-fused pyridazines 20 and 23 respectively.
Acetamides↗
Synthesis and molluscicidal activity of some 1,3,4-triaryl-5-chloropyrazole, pyrano[2,3-c]pyrazole, pyrazolylphthalazine and pyrano[2,3-d]thiazole derivatives.
2-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-malononitrile 1a reacts with the arylidenes of malononitrile 2a-d to afford the triaryl-5-chloropyrazoles 3a-d, respectively. 1a reacts with the active methylene pyrazolinones 5a, b and 12a, b to afford different products 8, 9, 10, 11, and 14a, b--depending on the substitution in the pyrazole ring. Compound 1a reacts also with the pyridazinone derivative 15 to afford the phthalazinone 16, and with the thiazolinones 17a-c to afford the pyrano[2,3-d]thiazoles 20a-c, respectively. It reacts also with the malononitrile dimer 21a and with ethyl cyanoacetate dimer 21b to yield the pyrazolyl pyridines 22a, b, respectively. The synthesized compounds showed a moderate molluscicidal activity towards Biomphalaria alexandrina snails.
Animals↗
Solid-state linear-dichroic IR-spectroscopy of isophorone derivatives with potential non-linear optical application.
Possibilities of linear-dichroic infrared (IR-LD) spectroscopy based on oriented solid samples as suspension in nematic liquid crystal have been applied for detailed experimental IR-band assignment and structural information of 2-[5,5-dimethyl-3-(2-phenyl-vinil)-cyclohex-2-enylidene]-malononitrile, 2-[5,5-dimethyl-3-[2-(2-methoxyphenyl)vinyl]cyclo-hex-2-enylidene]malononitrile and 2-[3-[2-(2,4-dimethoxyphenyl)vinyl]-5,5-dimethylcyclohex-2-enylidene]malononitrile. The data of last two compounds have been compared with known crystallographic ones, thus determining the validity of conclusions made.
Cyclohexanones↗
Thiourea-catalyzed asymmetric michael addition of activated methylene compounds to alpha,beta-unsaturated imides: dual activation of imide by intra- and intermolecular hydrogen bonding.
A thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to alpha,beta-unsaturated imides derived from 2-pyrrolidinone and 2-methoxybenzamide has been developed. In the case of 2-pyrrolidinone derivatives, the reaction with malononitrile proceeded in toluene with high enantioselectivity, providing the Michael adducts in good yields. However, the nucleophiles that could be used for this reaction were limited to malononitrile due to poor reactivity of the substrate. Further examination revealed that N-alkenoyl-2-methoxybenzamide was the best substrate among the corresponding benzamide derivatives bearing different substituents on the aromatic ring. Indeed, several activated methylene compounds such as malononitrile, methyl alpha-cyanoacetate, and nitromethane could be employed as a nucleophile to give the Michael adducts in good to excellent yields with up to 93% ee. The results of spectroscopic experiments clarified that this enhanced reactivity can be attributed to the intramolecular hydrogen-bonding interaction between the N-H of the imide and the methoxy group of the benzamide moiety. Thus, the key to the success of the catalytic enantioselective Michael addition is dual activation of the substrate by both intramolecular hydrogen bonding in the imide and intermolecular hydrogen bonding with thiourea 1a, as well as the activation of a nucleophile by the tertiary amine of the bifunctional thiourea.
Journal Article↗
Benzylidenemalononitrile derivatives as substrates and inhibitors of a new NAD(P)H dehydrogenase of erythrocytes. Purification and crystallisation of two forms of the enzyme.
Using the powerful lachrymator (2-chlorobenzylidene)malononitrile as electron acceptor, two types of NAD(P)H dehydrogenases have been isolated from human blood. Crystallisation of the homogenous enzymes was performed in 50% polyethylene glycol solution. The enzymes (average molecular weight 18 000) are composed of only one polypeptide chain and have a very similar amino acid composition. B-side stereospecificity was determined with respect to the cofactor by gas chromatography-mass spectrometry for the reductase. Besides (2-chlorobenzylidene)malononitrile, 2,6-dichloroindophenol, methylene blue, 4-benzoquinone, FMN and FAD are also reduced using NADH or NADPH as hydrogen donor with the rates decreasing in the given order. Reduction of methemoglobin is observed only upon addition of methylene blue, FMN or FAD as carriers. (2-Chlorobenzylidene)malononitrile reduction is inhibited by most of the compounds known to be decouplers of oxidative phosphorylation.
Amino Acids↗
Synthesis and antiproliferative activity of unsaturated quinoline derivatives.
In our previous work Knoevenagel condensation of quinoline 2-, 3- and 4-carbaldehyde with malononitrile derivatives was used to produce a series of heteroarylidene malononitrile derivatives. Some of these heteroaromatic tyrphostins were potent inhibitors of the epidermal growth factor (EGF) receptor kinase. This work has now been extended by using 6-, 7-, and 8-quinolinecarbaldehyde to prepare 23 new quinoline-tyrphostins 1-23. Most of these compounds were moderately active against the MCF7 breast cancer cell line. The order of potency was 7- > 6 > 8-substituted quinoline, which indicates that increased activity of the 7-substituted quinolines is associated with electron deficiency at the 7-position in the quinoline ring. The most active compound, 12, formed from 7-quinolinecarbaldehyde and ethyl cyanoacetate, had an IC50 value of 2.3 microM. Compounds 1-23 showed similar IC50 values against the MCF7 and MCF7/ADR cell lines (the latter shows fourfold increased protein tyrosine kinase activity) except for the compounds 1 and 15 formed from 6-quinolinecarbaldehyde and malononitrile and 7-quinolinecarbaldehyde and cyanoacetamide, which showed a significant (11- and 42-fold, respectively) increase in potency against the MCF7/ADR cell line. Furthermore, no association was found between growth inhibition and inhibition of the EGFR protein tyrosine kinase (PTK), using a cell-free assay. In addition, new compounds were prepared from 2- and 4-quinolinecarbaldehyde with extended conjugation in the side chains (24-27) or with methoxypolyethoxyethyl esters in the side chain to increase water solubility (28 and 29). These compounds showed substantial cytotoxicity, with IC50 values in the range 1-25 microM, but similar values were observed against both cell lines. No association was found between inhibition of PTK and growth inhibition, again indicating that their mode of action may not be specific for the EGF receptor.
Antineoplastic Agents↗
[Chemistry and pharmacology of pyran derivatives. XVII. Synthesis of 2-(dialkylamino)-5-hydroxychromones and their transformation to derivatives of 2H-pyran[4,3,2-de]-1-benzopyran].
Through the reaction of resorcin with N,N-dialkylethoxy-carbonylacetamides in suitable conditions 2-(dialkylamino)-5-hydroxychromones (II) were available. Transformation of these compounds into [5-acetoxy-2-(dialkylamino)-4H-chromen-4-ylidene] malononitriles (VII) by reaction with malononitrile in acetic anhydride and treatment of (VII) with hydrochloric acid gave rise to the formation of 5-(dialkylamino)-2-imino-2H-pyrano [4,3,2-de]-1-benzo-pyrans (VIII). Furthermore 5-hydroxychromones (II) when treated with methyl iodide gave the corresponding 5-methoxychromones (III) which in turn yielded 4H-chromen-4-ylidene derivatives (X) by reaction with malononitrile in acetic anhydride. The hydrolysis of the latter compounds with hydrochloric acid resulted in the formation of 2-(dialkylamino)-4-methyl-5-methoxychromenilium salts (XI). Among the compounds which were submitted to pharmacological screening for their antiallergic properties 5-methoxychromone (III a) and 2H-pyrano [4,3,2-de]-1-benzopyran (VIII b) showed a notable activity but also high toxicity.
Animals↗
Synthesis and molluscicidal activity of new cinnoline and pyrano [2,3-c]pyrazole derivatives.
2-(3-Hydroxy-5,5-dimethylcyclohexylidene)malononitrile 5 undergoes an azo coupling reaction with aryldiazonium salts to afford 3-amino-2-aryl-6,6-dimethyl-8-oxo-2,6,7,8-tetrahydrocinnoline-4-carbonitriles 7. Upon reflux in acetic acid, these compounds were acetylated to give the cinnoline derivatives 9. The pyrazolones 10a, b react with 3-furfurylidene- and 3-thienylidene-malononitrile derivatives 11a, b to afford the pyrano[2,3-c]pyrazole derivatives 13a-d. These newly synthesized compounds show generally a moderate molluscicidal activity to Biomphalaria alexandrina snails.
Animals↗
Structure-acute toxicity relationship of dinitriles in mice.
Acute toxicity and metabolism of seven dinitriles in mice was studied in relation to the chemical structures. The oral LD50 for each nitrile was determined under different conditions for mice pretreated with either carbon tetrachloride (CCl4) or olive oil. All test nitriles were metabolized into cyanide in vivo and in vitro. The cyanide level was variable among the compounds (0.35-0.74 micrograms CN/g brain) at death in the brains of mice, the level for malono- and adiponitrile being comparable to that found in mice killed by dosing with potassium cyanide. After receiving each nitrile, the mean survival time of mice pretreated with CCl4 was prolonged and their brain cyanide level decreased when compared with the corresponding control. With malononitrile, the former did not significantly change and the latter decreased slightly. Brain cyanide levels of control mice at death showed a peak at the lower log P region, while those of CCl4-pretreated animals remained lower independently of log P, with the exception of malononitrile. Microsomal metabolism of nitriles to cyanide was greatly inhibited when microsomes were prepared from livers of mice pretreated with CCl4. The relationship between log (1/LD50-CCl4), LD50 in mice pretreated with CCl4, and log P fits a parabolic plot.
Animals↗
Studies on aminopyrazoles: antibacterial activity of some novel pyrazol.
Hydrazones 2a-d were prepared from diazotiazation of sulfanilamide or its derivatives followed by coupling with ethyl cyanoacetate. 3-Aminopyrazoles 3a-d were obtained by refluxing of 2a-d with hydrazine hydrate in ethanol. [Bis(-methylthio)methylene]malononitrile (4) was reacted with aminopyrazoles 3a-d in refluxing DMF containing triethylamine to yield the novel pyrazolo[1,5-a]pyrimidines 6a-d. The anilino derivatives 8a-h were obtained by fusion of compounds 6a-d with aromatic amines. When compounds 6a,c,d were subjected to the reaction with hydrazine hydrate, the hydrazino derivatives 9a-c were isolated. Also, the aminopyrazoles 3 were reacted with some electrophiles such as arylidenemalononitriles, ethoxymethylene malononitrile and ethyl ethoxymethylene cyanoacetate to yield the novel substituted pyrazolo[1,5-a]pyrimidines 13, 17 and 19, respectively. Structures of the new compounds were established by their elemental analyses and spectral data. Most of these compounds were also tested in vitro for their antibacterial activity against some gram positive and gram negative bacteria.
Anti-Bacterial Agents↗
3D QSAR analyses of novel tyrosine kinase inhibitors based on pharmacophore alignment.
In an effort to develop a quantitative ligand-binding model for the receptor tyrosine kinases, a pharmacophore search was first used to identify structural features that are common in two novel sets of 12 molecules of the 3-substituted indolin-2-ones and 19 compounds of the benzylidene malononitriles with low-to-high affinity for HER2, a kind of receptor tyrosine kinase. The common pharmacophore model based on these 31 compounds was used as a template to obtain the aligned molecular aggregate, which provided a good starting point for 3D-QSAR analysis of only the 19 benzylidene malononitriles. Two molecular field analysis (MFA) techniques, including CoMFA and CoMSIA, were used to derive the quantitative structure-activity relationships of the studied molecules. From the studied results, it was obvious that the 3D-QSAR models based on the pharmacophore alignment were superior to those based on the simple atom-by-atom fits. Considering the flexibility of the studied molecules and the difference between the active conformers and the energy-lowest conformers, the pharmacophore model can usually provide the common features for the flexible regions. Moreover, the best CoMSIA model based on the pharmacophore hypothesis gave good statistical measure from partial least-squares analysis (PLS) (q(2) = 0.71), which was slightly better than the CoMFA one. Our study demonstrated that pharmacophore modeling and CoMSIA research could be effectively combined. Results obtained from both methods helped with understanding the specific activity of some compounds and designing new specific HER2 inhibitors.
Benzylidene Compounds↗
Solid-phase synthesis of 2-substituted 4-amino-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines: an example of cyclization-assisted cleavage.
An efficient solid-phase synthesis of 2-substituted 4-aminopyrido[2,3-d]pyrimidines 12 by cyclization-assisted cleavage from resin is reported. The procedure starts by solid supporting an alpha,beta-unsaturated acid 8 to the Wang resin 13 by using DCC and 4-DMAP in THF. The resulting alpha,beta-unsaturated ester 14 is converted to the Michael adduct by treatment with malononitrile in NaOMe/THF. Such Michael addition constitutes the first example of a Michael reaction with malononitrile in solid-phase. Finally, the Michael adducts 15 are treated with an amidine system in MeOH to yield the corresponding pyridopyrimidines 12. Compounds 12 present three diversity centers R1, R2 and G. Having validated the chemistry on solid support, a 40-membered combinatorial library was obtained using this protocol.
Combinatorial Chemistry Techniques↗
Condensation reactions of monomeric hydroxo palladium complexes with active methyl and methylene compounds.
Heating a suspension of the monomeric hydroxo palladium complex of the type [Pd(N-N)(C(6)F(5))(OH)](N-N = bipy, Me(2)bipy, phen or tmeda) in methylketone (acetone or methylisobutylketone) under reflux affords the corresponding ketonyl palladium complex [Pd(N-N)(C(6)F(5))(CH(2)COR)]. On the other hand, the reaction of the hydroxo palladium complexes [Pd(N-N)(C(6)F(5))(OH)](N-N = bipy, phen or tmeda) with diethylmalonate or malononitrile yields the C-bound enolate palladium complexes [Pd(N-N)(CHX(2))(C(6)F(5))](X = CO(2)Et or CN), and the reaction of [Pd(N-N)(C(6)F(5))(OH)](N-N = bipy or phen) with nitromethane gives the nitromethyl palladium complexes [Pd(N-N)(CH(2)NO(2))(C(6)F(5))]. [Pd(tmeda)(C(6)F(5))(OH)] catalyses the cyclotrimerization of malononitrile. The crystal structures of [Pd(bipy)(C(6)F(5))(CH(2)COMe)].1/2Me(2)CO, [Pd(tmeda)(C(6)F(5))[CH(CO(2)Et)(2)]], [Pd(tmeda)(C(6)F(5))[CH(CN)(2)]] and [Pd(tmeda)(C(6)F(5))(CH(2)NO(2))].1/2CH(2)Cl(2) have been established by X-ray diffraction.
Journal Article↗
Serotonin 1A receptors in the living brain of Alzheimer's disease patients.
4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT(1A)) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT(1A) receptor densities in the living brains of Alzheimer's disease patients (ADs) (n = 8), subjects with mild cognitive impairment (n = 6), and controls (n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 +/- 0.07; ADs 1.18 +/- 0.26) and also in raphe nuclei (controls 0.63 +/- 0.09; ADs 0.37 +/- 0.20). When volume losses are included, 5-HT(1A) losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT(1A) receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT(1A) receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro-d-glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 +/- 0.04, ADs 0.72 +/- 0.04; posterior cingulate gyrus: controls 1.05 +/- 0.09, ADs 0.79 +/- 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.
Alzheimer Disease↗