5-(Hydroxyimino)-4-methoxy-2-(pivaloylimino)thiazolidine-3-acetamide,a reduced nitroheterocyclic derivative with potent schistosomicidal properties

Summary The synthesis and antischistosome properties of 5-(hydroxyimino)-4-methoxy-2-(pivaloylimino)thiazolidine-3-acetamide (1) are described. The compound was prepared by reduction of the nitrothiazoline (2) with stannous chloride in methanol, and represents the first example of a reduced nitroheterocyclic compound showing potent schistosomicidal properties. The possible relationship of compounds such as1 to the as yet unidentified reduced active but toxic entities formed in vivo from nitroheterocyclics like metronidazole is discussed.Acknowledgments. The authors are grateful to Dr A. J. Everett and his staff for the physical chemistry measurements, and to Mr G. Dickerson for the antischistosome testing.     

Antiarrhythmic properties of 3-(2-hydroxy-3 isopropylamino-propoxy)-3 phenyl-2 isoindolinone-1, (RS, SR) in the dog]

In the Dog, 3-(2-hydroxy-3 isopropylamino-proxy)-2-phenyl-1-isoindolinone (RS, SR) possesses an anti-arrhythmic activity similar to that of quinidine but at dose levels 2 to 6 times lower than in the case of the latter compound. Furthermore, in contrast to quinidine, at the dose levels where the antiarrhythmic activity is well observed, the compound is devoid of hypotensive activity and of depressive action on cardiac contractility. The first clinical studies of this compound have shown its usefulness in the treatment of ventricular and supraventricular arrhythmias.     

Protective effect of N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine (PF9601N) on mitochondrial permeability transition

PF9601N, N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine, an monoamine oxidase (MAO) B inhibitor, has shown neuroprotective properties against dopaminergic toxins. To elucidate the mechanisms involved in this protection, the effect of PF9601N on mitochondria was assessed. PF9601N prevents mitochondrial swelling, drop in the electrical potential and oxidation of sulfhydryl groups, glutathione and pyridine nucleotides induced by Ca²⁺. These observations demonstrate the protective effect of PF9601N on the induction of mitochondrial permeability transition. This protection is due to the interaction of the secondary protonated amino group in the molecule with pore-forming structures and to its antioxidant property, rather than to inhibition of MAO B activity. PF9601N also prevents the release of cytochrome c from mitochondria, suggesting its potential inhibitory effect on mitochondria-mediated apoptosis. The low IC⁵⁰ value for this inhibition, in comparison with deprenyl, make it a more efficient compound than propargylamines and other amines in protecting the bioenergetic functions of mitochondria. Received 9 March 2006; received after revision 10 April 2006; accepted 21 April 2006     

The efficacy of a novel compound, (E)-1-(4′-bromo-4-biphenylyl)-1-(4-chlorophenyl)-3-dimethylaminoprop-1-ene againstTrypanosoma cruzi in mice

Summary The biological properties of a novel compound 353C with high activity againstTrypanosoma cruzi, are described. The compound was about 10 times and 20 times more effective than either benznidazole or nifurtimox respectively, in producing radical cure in mice. 353C had a long half-life and showed anti-trypanosomal properties when given to mice at weekly intervals.     

Antihypertensive and other cardiovascular effects of 2-(3-pyridyl)- and 2-(4-pyridyl)-4-trifluoromethylimidazoles.

2 new 4-trifluoromethylimidazole derivatives were found which lowered mean arterial pressure in renal and spontaneously hypertensive (SH) rats by the oral route. In SH rats, compounds A and B were 0.1 and 0.3 times, respectively, as potent as hydralazine. No tolerance development was observed in SH rats with either compound over a 1-week period. In anesthetized dogs, both compounds lowered arterial pressure and peripheral vascular resistance but increased cardiac output. By intraarterial administration, both compounds increased femoral arterial blood flow. These findings represent discovery of a new class of vasodilator durgs.     

Antihypertensive and other cardiovascular effects of 2-(3-pyridyl)- and 2-(4-pyridyl)-4-trifluoromethylimidazoles

Summary 2 new 4-trifluoromethylimidazole derivatives were found which lowered mean arterial pressure in renal and spontaneously hypertensive (SH) rats by the oral route. In SH rats, compounds A and B were 0.1 and 0.3 times, respectively, as potent as hydralazine. No tolerance development was observed in SH rats with either compound over a 1-week period. In anesthetized dogs, both compounds lowered arterial pressure and peripheral vascular resistance but increased cardiac output. By intraarterial administration, both compounds increased femoral arterial blood flow. These findings represent discovery of a new class of vasodilator drugs.Deceased, May 31, 1978.     

7-Chloro-3-(4-methyl-1-piperazinyl)-4H-1,2,4-benzothiadiazine-1,1-dioxide a new antihypertensive agent

Summary 7-Chloro-3-(4-methyl-1-piperazinyl)-4H-1,2,4-benzothiadiazine-1,1-dioxide (DU-717) is a new compound having sustained antihypertensive activity in a similar manner to that of hydrochlorothiazide. However, this compound shows neither diuretic nor hyperglycemic effect, being different from those of hydrochlorothiazide or diazoxide.     

(R)-(Z,E)-9,11-octadecadien-13-olide: An intriguing lactone fromHeliconius pachinus (Lepidoptera)

Summary A fourteen-membered lactone,(R)-(Z,E)-9,11-octadecadien-13-olide, was isolated from extruded abdominal glands of a Neotropical, nymphalid butterfly,Heliconius pachinus (Lepidoptera). This compound was obtained from mature adults of both sexes, but was not detected in young adults or pupae.     

Pharmacological studies of a new analgesic,dl-erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride,in experimental animals

Summary dl-Erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride showed orally a definite analgesic activity, without producing the significant morphine-like physical dependence liability, and its analgesic potency was about a half that of codeine and far superior to aminopyrine in experimental animals.     

Glucagon-like peptide-1(1-37) inhibits chemokine-induced migration of human CD4-positive lymphocytes

The present study examined the effect of GLP-1(1-37) on chemokine-induced CD4-positive lymphocyte migration as an early and critical step in atherogenesis. Pretreatment with GLP-1(1-37) reduced the SDF-induced migration of isolated human CD4-positive lymphocytes in a concentration-dependent manner. Similar effects were seen when RANTES was used as a chemokine. GLP-1(1-37)’s effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity. Downstream, GLP-1(1-37) inhibited SDF-induced phosphorylation of MLC and cofilin and limited f-actin formation as well as ICAM3 translocation. Furthermore, exendin-4 inhibited SDF-induced migration of CD4-positive lymphocytes similarly to GLP-1(1-37), and transfection of these cells with GLP-1 receptor siRNA abolished GLP-1(1-37)’s action on chemokine-induced ICAM3 translocation, suggesting an effect mediated via the GLP-1 receptor. Thus, GLP-1(1-37) inhibits chemokine-induced CD4-positive lymphocyte migration by inhibition of the PI3-kinase pathway and via the GLP-1 receptor. This effect provides a potential novel mechanism for how GLP-1(1-37) may modulate vascular disease.     

Pharmacological studies of a new analgesic, dl-erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride, in experimental animals.

dl-Erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride showed orally a definite analgesic activity, without producing the significant morphine-like physical dependence liability, and its analgesic potency was about a half that of codeine and far superior to aminopyrine in experimental animals.     

Effect of imazalil (1-(2-(2,4-dichlorophenyl)-2-(2-propenyloxy) ethyl)-1H-imidazole) on biosynthesis of ergosterol in Penicillium expansum Link]

Imazalil is a new fungicide effective against Penicillium molds on fruits after harvest. This compound inhibits ergosterol biosynthesis in mycelia of Penicillium expansum. The accumulation of 24--methylenedithydrolanosterol, obtusifoliol and 14 alpha-methyl-delta 8, 24(28)-ergostadienol in treated fungi suggests that imazalil blocks sterol C--14 demethylation.     

(-)-(R)-1-O-Geranylgeranylglycerol from the brown alga Dilophus fasciola

Summary A novel ether lipid, (-)-(R)-1-O-geranylgeranylglycerol (1), has been isolated from the brown alga Dilophus fasciola and its structure proved by spectroscopic methods and chemical degradation.This work was supported by CNR, Rome, Italy.     

Synthesis of (Glu-OMe)2-litorin

Summary The synthesis of the nonapeptide2, corresponding to the formula of the (Glu-OMe)²-litorin, is described. The compound has the same chemical and biological properties of the second bombesin-like peptide extracted from the skin of the Australian frog Litoria aurea.     

New C26 delta-lactones from the Dufour's gland of the urticating ant Tetramorium aculeatum.

(6R*)-[(2S*)-2-hydroxyheneicos-12-enyl]-5,6-dihydro-2H-pyran-2-one (1) degree is the major constituent of the secretion of freshly dissected Dufour's gland of the urticating ant Tetramorium aculeatum. In solution, compound 1 is slowly transformed into (1S*,5R*,7S*)-7-(nonadec-10-enyl)-2,6-dioxabicyclo[3.3.1] nonan-3-one (2) degrees on standing. The structures of compounds 1 and 2 have been established on the basis of their spectral and chemical properties. Compound 1 could be responsible for the urticating properties of the ant.     

Antihypertensive agents III. Synthesis and antihypertensive activity of 3-[4-(p-fluoro-phenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-[1-(2-hydroxyethyl)-5-methyl-4-pyrazolyl]-1-propanone

Zusammenfassung 3-[4-(p-Fluorphenyl)-1,2,3,6-te-trahydro-1-pyridyl]-1-[1-(2-hydroxyaethyl)-5-methyl-4-pyrazolyl]-1-propanon (I, CIBA 4416/B-Go) senkt bei normotonischen und hypertonischen Tieren den Blutdruck. Die Drucksenkung kann hauptsächlich auf die periphere Vasodilatation sowie auf die Vasomotorenzentren bezogen werden. Ausserdem wirkt CIBA 4416/B-Go adrenolytisch.

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Previous paper:V. P. Arya, R. S. Grewal, C. L. Kaul, S. P. Ghate, D. V. Mehta andT. George, J. Pharm. Sci.58, 432 (1969).Contribution No. 243 from CIBA Research Centre.     

(-)-Dihydromylione A,a novel tetracyclic sesquiterpene ketone containing two conjugated cyclopropane rings,from Mylia taylorii (liverwort)

Summary A novel tetracyclic sesquiterpene ketone named (-)-dihydromylione A (III) was isolated from the liverwort, and the structure was determined together with the absolute configuration to be ent-5, 10-cyclo-aromadendr-3-one by connecting the compound with co-occurring (-)-myliol (II).     

The metabolism of dibenz[b,f]-1,4-oxazepine (CR): in vivo hydroxylation of 10,11-dihydrodibenz[b,f]-1,4-oxazepin-11-(1OH)-one and the NIH shift

Studies of the in vivo metabolism of 10,11-dihydrodibenz[b,f]-1,4-oxazepin-11-(1OH)-one (2) specifically deuteriated at C7 implicate an arene oxide intermediate during the conversion to 7-hydroxy-2 (4) as evidenced by the observation of the NIH shift.     

(S)-(+)-4,4,4-Trifluoro-3-(indole-3-)butyric acid,a novel fluorinated plant growth regulator

Racemic 4,4,4-trifluoro-3-(indole-3-)butyric acid (TFIBA) has been synthesized and shown to inhibitAvena coleoptile elongation. (S)-(+)-TFIBA (fig. 1), which was prepared by an enzymatic method and markedly promotes root growth of Chinese cabbage, lettuce and rice plants, is a novel fluorinated plant growth regulator. Activity of the (S)-(+)-enantiomer of TFIBA was 10-fold greater than that of the (R)-(–)-enantiomer in the first two plant species and 5-fold greater in rice.     

A peculiar fatty acid, (Z,Z)-9,12,17-octadecatrienoic acid,identified in the phospholipids of the pea aphid,Acyrthosiphon pisum (Harris) (homoptera: aphididae)

A peculiar fatty acid previously detected in the phospholipids of the pea aphid,Acyrthosiphon pisum, is identified as (Z,Z)-9,12,17-octadecatrienoic acid. It is the first report of this compound in the literature. Comparison of fatty acid profiles of phospholipids between normal and aposymbiotic pea aphids shows that aphid symbionts are not responsible for the biosynthesis of this unusual fatty acid.