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PubMed1999

In vitro leishmanicidal activity of aurones.

A series of aurones with drug-potential for Leishmania infections was identified in vitro using both a direct cytotoxicity assay against extracellular promastigotes of Leishmania donovani, L. infantum, L. enriettii, and L. major, and a test against intracellular amastigote forms of L. donovani residing within murine macrophages. The most active aurone (6-hydroxy-2-[phenylmethylene]-3(2H)-benzofuranone) had an EC50 of 0.45 microgram/ml in the extra-, and an EC50 of 1.40 micrograms/ml in the intracellular assay. Other aurones were active between 0.06-12.50 micrograms/ml and 0.04-7.81 micrograms/ml, respectively. When tested against murine bone marrow-derived macrophages as a mammalian host cell control, the compounds showed only moderate cytotoxicity (EC50 2.32 to > 25.0 micrograms/ml). This is the first report on aurones as a new class of natural products with leishmanicidal activity.

Animals↗
PubMedDate not supplied

Synthesis and beta-adrenergic activity of a series of 3-(substituted-benzylideneaminoxy)propanolamine derivatives.

In an attempt to change the beta-adrenergic properties of completely aliphatic 3-(methyleneaminoxy)propanolamine derivatives, from antagonist to agonist, while still retaining the beta 2-selectivity, we described, in a previous paper, the synthesis of a series of such derivatives possessing a hydroxy or methoxy group linked to the aliphatic substituent present on the oximic carbon. However, pharmacological tests indicated that these compounds maintain the competitive antagonism on beta receptors. In this paper, the synthesis and the results of functional tests on isolated preparations are reported for a new series of 3-(substituted-benzylideneaminoxy)propanolamine derivatives in which either the hydroxy or the methoxy group is linked to a phenyl ring present on the oximic carbon. The results obtained are then discussed, taking into account the conformational and reactivity properties of these compounds, determined by means of theoretical calculations.

Adrenergic beta-1 Receptor Agonists↗
PubMed2006

Design and synthesis of N-(3,3-diphenylpropenyl)alkanamides as a novel class of high-affinity MT2-selective melatonin receptor ligands.

A novel series of melatonin receptor ligands was discovered by opening the cyclic scaffolds of known classes of high affinity melatonin receptor antagonists, while retaining the pharmacophore elements postulated by previously described 3D-QSAR and receptor models. Compounds belonging to the classes of 2,3- and [3,3-diphenylprop(en)yl]alkanamides and of o- or [(m-benzyl)phenyl]ethyl-alkanamides were synthesized and tested on MT(1) and MT(2) receptors. The class of 3,3-diphenyl-propenyl-alkanamides was the most interesting one, with compounds having MT(2) receptor affinity similar to that of MLT, remarkable MT(2) selectivity, and partial agonist or antagonist behavior. In particular, the (E)-m-methoxy cyclobutanecarboxamido derivative 18f and the di-(m-methoxy) acetamido one, 18g, have sub-nM affinity for the MT(2) subtype, with more than 100-fold selectivity over MT(1), 18f being an antagonist and 18g a partial agonist on GTPgammaS test. Docking of 18g into a previously developed MT(2) receptor model showed a binding scheme consistent with that of other antagonists. The MT(2) expected binding affinities of the new compounds were calculated by a previously developed 3D-QSAR CoMFA model, giving satisfactory predictions.

Acetamides↗
PubMed1991

Studies on the antibacterial action of novel gem-diphenyl-spiro-cyclopropano- oxazolones and 2-aryl(alkyl)-4-ylidene-oxazol-5-ones.

The preparation and in vitro antibacterial activity of a novel series of gem-diphenyl-spiro-cyclopropano-oxazolones (cis-1,2,2,5-tetraphenyl 6-oxa-4-azaspiro[2.4]hept-4-en-7-one) are described. The overall activity of these compounds was higher than that of the 2-aryl(alkyl)4-ylidene-oxazol-5-ones (azlactones). The gem-diphenyl-spiro-cyclopropano-oxazolones 1-4 have emerged as the most potent derivatives when tested against bacteria.

Anti-Bacterial Agents↗
PubMed1996

Inhibition of plasminogen activator inhibitor-1 activity by two diketopiperazines, XR330 and XR334 produced by Streptomyces sp.

Two diketopiperazines, XR334 (1) and the novel compound XR330 (2), were isolated from the lyophilised biomass of an unidentified Streptomyces sp. Their structures were elucidated on the basis of spectroscopic studies and confirmed by chemical synthesis. Both compounds inhibited plasminogen activator inhibitor-1 activity in an amidolytic assay of tissue plasminogen activator mediated plasmin generation. Compound 1 also enhanced fibrinolysis ex vivo and protected against thrombus formation in the rat. These diketopiperazines represent the first low molecular weight inhibitors of plasminogen activator inhibitor-1, a physiological regulator of fibrinolysis.

Animals↗
PubMedDate not supplied

Encapsulated liquid crystals as probes for remote thermometry.

A temperature probe based on the magnetic resonance properties of an encapsulated liquid crystal has been investigated. Large changes in magnetic resonance signals occur as the liquid crystal undergoes a phase transition from an anisotropic (nematic) state to the isotropic liquid. The low latent heat of such phase transitions allows for rapid phase changes during a hyperthermia treatment. Transition temperatures can be tailored by adding suitable compounds such as analogues of the liquid crystal or various solvents. Encapsulation is required to maintain the integrity of the liquid crystal, particularly for applications in vivo. Results of preliminary studies designed to demonstrate the technical feasibility of the concept are presented.

Benzylidene Compounds↗
PubMedDate not supplied

Radical intensity and carcinogenic activity of benz[c]acridines.

Among 13 benz[c]acridines, six 7-methyl-substituted compounds (7-methylbenz[c]acridine, 7,9-dimethylbenz[c]acridine, 7,10-dimethylbenz[c]acridine, 7,11-dimethylbenz[c]acridine, 7,9,10-trimethylbenz[c]acridine, 7,9,11-trimethylbenz[c]acridine) were carcinogenic, while the other seven compounds (benz[c] acridine, 8-methylbenz[c]acridine, 9-methylbenz[c]acridine, 10-methylbenz[c]acridine, 11-methylbenz[c]acridine, 5,7-dimethylbenz[c]acridine, cis-5,6-dihydroxy-5,6-dihydrobenz[c]acridine) were inactive. Using both McLachlan-Hückel molecular orbital (McLachlan-HMO) and HMO methods, all the carcinogenic compounds were shown to have the elevated pi-spin density at 12th nitrogen atom of their molecules, as compared with noncarcinogenic compounds. Electron spin resonance (ESR) spectroscopy, however, revealed that both carcinogenic and noncarcinogenic compounds produced no detectable amounts of radical. This is in contrast to ascorbates, gallates and benzo[a]phenothiazines, which induced apoptosis by radical mediated mechanism(s). Amino acid analysis demonstrated that methionine oxidation is not involved in the induction of carcinogenic activity by benz[c]acridines.

Acridines↗
PubMed1987

Synthesis and antiinflammatory activities of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-ones.

A series of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-ones was synthesized and evaluated as candidate antiinflammatory/analgesic agents as well as dual inhibitors of prostaglandin and leukotriene synthesis. Some compounds that showed dual inhibitory activity were found to possess equipotent antiinflammatory activities to indomethacin, with reduced ulcerogenic effects. One of the compounds, N-methoxy-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-o ne, was found to have a wider safety margin than indomethacin or piroxicam, and was selected for detailed evaluation as a candidate drug for clinical application.

Animals↗
PubMed1987

2-Arylidene-4-cyclopentene-1,3-diones designed as non-nitro radiosensitizers and hypoxic cytotoxins.

The radiosensitizing effects and hypoxic cytotoxicity of 2-(4'-hydroxybenzylidene)-cyclopentene-1,3-dione (KIH-200) and its 3'-methoxy and 3',5'-dimethoxy derivatives (KIH-201 and KIH-202) were investigated in vitro. These synthetic compounds were newly designed as non-nitro electron-affinic radiosensitizers and hypoxic cytotoxins on the basis of their high electron affinities and electrostatic potentials which were estimated by semiempirical molecular orbital calculation using the CNDO/2 program. The compounds were shown to have weak but apparent hypoxic cytotoxicity to FM3A cells from C3H mice. On irradiation in the presence of KIH-201 or KIH-202, hypoxic cells were more sensitive than aerobic cells at very low drug concentrations (below 10 microM), whereas KIH-200 was less effective.

Animals↗
PubMed1976

Synthesis of N,N'-bis(3-substituted benzylideneaminopropyl)-piperazines and their anti-inflammatory, antiproteolytic, and anticonvulsant properties.

Some N,N'-bis(3-substituted benzylideneaminopropyl) piperazines were synthesized and characterized by their sharp melting points and elemental analyses. These substituted piperazines possessed anti-inflammatory activity, and the protection afforded by these compounds against carrageenan-induced edema ranged from 23 to 67%. The antiproteolytic activity of these piperazines was reflected by their ability to inhibit in vitro hydrolysis of bovine serum albumin and casein by trypsin. The inhibition of trypsin-induced hydrolysis was concentration dependent and competitive in nature.

Animals↗
PubMed1991

Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases.

We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins. The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalononitrile moiety. In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides. Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2). These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.

Benzylidene Compounds↗
PubMed1979

Monoamine oxidase inhibition by substituted benzylideneamino guanidines and their CNS activities.

The present study reports the synthesis and characterization of eight new substituted benzylideneamino guanidines. All compounds inhibited the monoamine oxidase (MAO) activity of rat brain mitochondria in vitro. The I50 values were determined and were found to be in the range of 10(-4) to 10(-5) mol/l. Preincubation, dialysis and kinetic studies carried out with isolated brain mitochondria by conventional Dixon plot revealed reversible and noncompetitive type of MAO inhibition. These compounds were also screened for anticonvulsant and antidepressant activities. In the present series of compounds only one compound -- 1-amino-3-(4-chloromethylbenzylidene-amino)guanidine hydroiodide -- was found to afford 20% protection against pentetrazol-induced seizures in mice. 1-Amino-3-(3,4-dichlorobenzylideneamino)guanidine hydroiodide which produced maximum inhibition of MAO activity, also produced reversal of reserpine-induced sedation and miosis into excitation and mydriasis in mice.

Animals↗
PubMed2002

Prediction of plasma concentration of GTS-21 in hairless rats following monolithic transdermal delivery.

The transdermal therapeutic systems (TTS) usually achieve constant plasma concentration for an extended period of time. This is because a sufficient drug stored in the device can keep the constant concentration on the surface of the stratum corneum during the system application. When the drug molecules are not enough to provide the constant surface concentration, the rate of drug penetration decreases with time because of decreased supply of the drug molecules from the delivery device. This paper has proposed an empirical simple approach to predict the plasma concentration for such a TTS. A novel compound, GTS-21, for Alzheimers' disease currently under development was used as a model drug. In vivo and in vitro experiments were carried out in hairless rats. The in vivo plasma concentration-time profile in hairless rats following the application of TTS well agreed with the predicted profile based on the skin pharmacokinetic model together with the model parameters determined from the in vitro experiment.

Administration, Cutaneous↗
PubMed1996

Tyrphostins. 6. Dimeric benzylidenemalononitrile tyrophostins: potent inhibitors of EGF receptor tyrosine kinase in vitro.

Benzylidenemalononitrile (BMN) tyrphostins were previously found to be potent inhibitors of EGF receptor (EGFR) tyrosine kinase activity. Since these compounds were found to compete for the substrate and sometimes with the ATP site and since EGFR acts as a dimer, we prepared a series of dimeric tyrphostins. These dimeric tyrphostins were built from two BMN units linked by various spacers and designed to fit the dimeric cross-autophosphorylation signal transduction intermediate of the EGFR tyrosine kinases. Structure-activity relationship of these potent dimeric EGF receptor tyrosine kinase inhibitors is reported.

Benzylidene Compounds↗
PubMed1994

Synthesis of naltrexone-derived delta-opioid antagonists. Role of conformation of the delta address moiety.

Naltrindole (1) (NTI) is a highly potent and selective delta-opioid receptor antagonist. In an effort to understand the origin of the high potency, affinity, and selectivity of NTI, we have examined the conformational role of its indolic benzene moiety through the synthesis of related naltrexone derivatives 3-8, which contain the benzene moiety in different orientations and at different attachments in the molecule. One of these naltrexone derivatives, 5, whose 7-indanyl benzene moiety is orthogonal to ring C of the morphinan system, is a potent delta-opioid receptor antagonist in vitro and in vivo. Computer-assisted molecular overlay studies of the minimized structures (2-8) revealed the importance of the position of the benzene moiety for effective interaction with delta-opioid receptors. In compounds 2, 4, and 5, the aromatic ring falls in the same region of space as that of the indolic benzene moiety of NTI, and all of these ligands possessed significant activity at delta-opioid receptors. Analogues (3 and 6-8) which were shown to have relatively weak delta-opioid receptor antagonist potency have their aromatic groups located in a space that is different from that of the more potent analogues.

Animals↗