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PubMed2003

Synthesis, conformational analysis and free radical scavenging activity of some new spiropyranoquinolinones.

A series of novel spiroadamantyl- and spirocyclical substituted pyranoquinolin-2-ones were synthesized and the conformation of the pyran ring was investigated. The free radical scavenging activity of the synthesized compounds was determined by their interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). All compounds tested scavenged the DPPH radical and among them derivatives possessing extended conjugation showed the highest activity.

Biphenyl Compounds↗
PubMed2001

Siramesine H Lundbeck.

Siramesine is a sigma2 opioid agonist under development by H Lundbeck as a potential treatment for anxiety 11678721. In March 1998, the compound was licensed to Forest Laboratories under a strategic alliance [282593]. In August 2000, siramesine entered phase II trials [378814]. Phase III trials are expected to take place in 2002 [387270]. A series of compounds have been synthesized by Lundbeck, the most potent of which may serve as a backup compound [179036].

Animals↗
PubMed2006

Photochemistry of o-pyrrolylstilbenes and formation of spiro-2H-pyrroles and their rearrangement to dihydroindoles.

Excited states of stilbenylpyrroles 1a-1c deactivate by two photochemical processes: cis-trans-isomerization and hydrogen transfer of NH to the stilbene double bond. NH-transfer results in the formation of two quinone dimethane intermediates, 10 and 11, and biradicals 12. Intramolecular cyclization of intermediates 10-12 gives rise to polycyclic compounds spiro-2H-pyrroles 7, pyrroloisoindoles 3, and pyrroloisoquinolines 8. Spiro-2H-pyrroles 7 rearrange on silica gel, giving dihydroindoles 2.

Journal Article↗
PubMed2004

Syntheses of potential metabolites of a potent kappa-opioid receptor agonist, TRK-820.

Chemical syntheses of three kinds of potential metabolites of TRK-820, a potent kappa-opioid receptor agonist, were described. One of the potential metabolites 2, 17-N-dealkylated TRK-820, was synthesized starting from noroxycodone through 8 steps in 21% total yield. Glucuronidation of intermediate 10 and compound 1, the free base of TRK-820, was carried out stereoselectively to give 3-O-beta-D-glucuronides 15 and 16 in good yields, respectively. Syntheses of potential conjugated metabolites 3 and 4 were accomplished through 10 steps and 2 steps in 11% and 43% total yields, respectively. Among the potential metabolites of TRK-820, compounds 2 and 4 were identified as metabolites in human hepatocytes. The results of pharmacological studies of compounds 2, 3, and 4 are described.

Hepatocytes↗
PubMed1988

[A new series of antiparasitic organic arsenicals: the spiroarsoranes. Experimental trypanocidal activity].

Arsenical compounds are the main therapeutic way, effective in the neurological phase of trypanosomiasis. Unfortunately, their important toxicity prevents their easy administration. Structural cyclization of arsonic acid derivatives has led to a class of non-toxic compounds: spiroarsoranes. A 47 compound primary screening on an in vivo murine model of Trypanosoma brucei brucei resulted in the isolation of a very effective derivative after a single subcutaneous injection of 30 mg.kg-1 body weight (Chemotherapeutic Index = 21). In this study, trypanocidal activity of this compound was evaluated on an in vivo sheep model of trypanosomiasis by T. brucei brucei, according to experimental model of the Institute of Neurological Epidemiology and Tropical Neurology of Limoges (France). A single subcutaneous injection of 30 and 100 mg.kg-1 b.w., and 30 and 60 mg.kg-1 b.w. was given respectively during first and second phase of trypanosomiasis. Ovine pharmacokinetics of this compound will be evaluated in a further study.

Animals↗
PubMed2000

The ability of WAY100,635 to potentiate the neurochemical and functional actions of fluoxetine is enhanced by co-administration of SB224,289, but not BRL15572.

The present study employed a combined neurochemical and behavioural approach to address the question of whether blockade of (presynaptic) 5-HT(1B) or 5-HT(1D) receptors enhances the facilitatory influence of 5-HT(1A) autoreceptor antagonism upon the actions of selective serotonin re-uptake inhibitors (SSRI). In the presence of the selective 5-HT(1A) antagonist, WAY100,635, the fluoxetine-induced increase in dialysate levels of 5-HT in the frontal cortex (FCX) of freely-moving rats was significantly potentiated. The selective 5-HT(1B) antagonist, SB224,289, likewise potentiated the increase in 5-HT levels evoked by fluoxetine. Further, administered together, WAY100,635 and SB224,289, at least additively, potentiated the influence of fluoxetine upon 5-HT levels. This effect was selective inasmuch as, either alone or together, WAY100,635 and SB224,289 did not modify the influence of fluoxetine upon FCX levels of dopamine (DA) or noradrenaline (NA) quantified in the same dialysis samples. Co-administration of SB224,289 also enhanced the ability of WAY100,635 to potentiate the induction of head-twitches (HTW) by fluoxetine. This response reflects activation of 5-HT(2A) sites in FCX and was abolished by the selective 5-HT(2A) antagonist, MDL100,907. In contrast to SB224,289, the 5-HT(1D) antagonist, BRL15572, failed to enhance the facilitatory influence of WAY100,635 upon the neurochemical or behavioural actions of fluoxetine. In conclusion, co-joint blockade of 5-HT(1B) - but not 5-HT(1D) - with 5-HT(1A) autoreceptors markedly potentiates the neurochemical and functional actions of the SSRI, fluoxetine.

Animals↗
PubMed2004

Identification of an antimalarial synthetic trioxolane drug development candidate.

The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which--the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)--may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chemical (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.

Animals↗
PubMed1999

Synthesis of (1-azabicyclo[3.3.0]octanyl)methyl-substituted aromatic heterocycles and their muscarinic activity.

In our development of drugs effective against Alzheimer's disease, we have researched a series of aromatic compounds having a characteristic cyclic amine, 1-azabicyclo[3.3.0]octane ring. In this report, we describe synthesis of a series of aromatic heterocycles with the 1-azabicyclo[3.3.0]octane ring and their pharmacological evaluation. 3-Amino-5-(1-azabicyclo[3.3.0]octan-5-yl)methyl-1,2,4-oxadiazole (2b) showed the highest M1 selectivity.

Animals↗
PubMed1977

Hepatic effect of two hypolipidemic drugs in rats.

Some hepatic effects of the hypolipidemic agents 3,9-di-3-pyridyl-2,4,8,10-tetraoxaspiro-5,5-undecane (compound A) and 2-(4-dibenzofuranyloxy)-2-methylpropionic acid (compound B) were investigated in male rats. The animals were treated orally with these drugs and a reference compound-clofibrate for 10 weeks, the daily doses being 250, 300 and 300 mg/kg body weight respectively. All three drugs caused hepatomegaly with a normal microscopic appearance in liver cells. In rats given compound A, part of some liver cells could be occupied by numerous membranes of smooth endoplasmic reticulum. The hepatocytes of the rats treated with compound B or clofibrate showed a marked increase in microbody profiles and an elevated hepatic catalase activity in comparison to the control animals. Neither the microbodies nor the catalase activity were affected by compound A. Hypolipidemic effects were demonstrated with all three compounds, the most potent activity being shown by compound B. Treatment with this agent resulted in significantly higher catalse activity than with clofibrate.

Animals↗
PubMed1976

Oxindole-3-spiropyrrolidines and -piperidines. Synthesis and local anesthetic activity.

The synthesis and local anesthetic properties of five 1-dealkyloxindole-3-spiropyrrolidines and six 1-dealkyloxindole-3-spiropiperidines are described. The compounds studied include members of all five possible positional isomers of the two classes of spirooxindoles; all showed local anesthetic activity by the rat sciatic nerve block method. The coincidence of the least variability in the relative positions of basic nitrogen, amide carbonyl, and aromatic ring (compounds 1 and 6) with lowest normalized toxicity is noteworthy.

Anesthetics, Local↗
PubMed2002

Thiersinines A and B: novel antiinsectan indole diterpenoids from a new fungicolous Penicillium species (NRRL 28147).

[structure: see text] Two novel antiinsectan indole diterpenoids, thiersinines A (1) and B (2), along with seven known paxilline-type compounds, were isolated from organic extracts of a new Penicillium species (P. thiersii NRRL 28147). The structures of 1 and 2 were determined by analysis of 2D NMR data. Thiersinines A and B possess a unique spirocyclic subunit that is unprecedented in previously known compounds of this class. Both compounds exhibit potent activity against the fall armyworm (Spodoptera frugiperda).

Animals↗
PubMed2005

Synthesis of the core structure of acutumine.

[reaction: see text] The tricyclic core of the bioactive natural product acutumine has been synthesized. Key steps include an oxidative phenolic coupling to form a masked o-benzoquinone, an anionic oxy-Cope rearrangement to construct an all-carbon quaternary center, and a Michael-type cyclization to form an amine-bearing quaternary carbon. The target compound exists in solution as an enol, in contrast to related compounds that are ketones. A model explaining these observations is presented.

Alkaloids↗
PubMed2002

[Determination of nanchangmycin and meilingmycin by high performance liquid chromatography].

A high performance liquid chromatographic method had been established for the separation and determination of two antibiotics produced by Streptomyces nanchangensis, polyether nanchangmycin and 16-membered macrolide meilingmycin. The latter is composed of several components. The operating conditions were Waters XTerra RP18 column (3.9 mm i.d. x 150 mm, 5 microns) at 25 degrees C, mobile phase linear gradient elution of acetonitrile-water with 57:43 (volume ratio) during 0 min-30 min, 70:30 during 30 min-32 min, 80:20 during 32 min-34 min, 90:10 during 34 min-50 min at a flow rate of 0.8 mL/min, and photodiode array detector at 234 nm. This method is accurate, rapid and simple, and can be used for the integrated analysis of the two different natural compounds, polyethers and macrolides.

Anti-Bacterial Agents↗
PubMed1993

Spiroarsoranes of second generation: evaluation of trypanocidal properties against Trypanosoma brucei brucei.

The spiroarsoranes are a series of pentavalent arsenicals having interesting trypanocidal properties. They are less toxic than trivalent arsenicals but their activity appear at higher doses and concentrations. The structure-activity relationships study from the first series led to a new generation of spiroarsoranes which has been synthesized and evaluated in vitro and in vivo against Trypanosoma brucei brucei bloodstream forms. Among 40 compounds, 5 were active in vitro at concentrations less than 10 mumol/l and 7 were active in vivo. The most interesting compound of this series (compound I e 2) showed an in vitro activity at 125 mumol/l after 24 hours incubation time and in vivo all the mice were cured after a subcutaneous treatment at 600 mumol/kg in one single dose. The spiranization and the substitution of para-arsanilic acid allowed to obtain a better mean survival time at 300 mumol/kg comparatively to para-arsanilic acid itself used as reference compound. Nevertheless, this second generation of compounds was less active than the selected compound of the first series which was efficient at 150 mumol/kg in subcutaneously one single dose.

Animals↗