Synthesis, benzodiazepine receptor binding and molecular modelling of isochromeno[4,3-c]pyrazol-5(1H)-one derivatives.

A series of isochromeno[4,3-c]pyrazole-5(1H)-one derivatives 7b-h were prepared and tested at 10 µM for their ability to displace specific [(3)H]flunitrazepam from bovine brain membranes. The substitution pattern of the above derivatives was shown to influence the receptor affinity. The most active compound of the series was 7e, showing a 54% inhibition of [(3)H]flunitrazepam binding. Compounds 7a-d,i were compared with the known isomers chromeno[4,3-c]pyrazole-4(1H)-ones 14a-d,i, showing that the isochromene/chromene isomerism influences the activity.

Perinatal exposure to 5-methoxytryptamine, behavioural-stress reactivity and functional response of 5-HT1A receptors in the adolescent rat.

Serotonin is involved in a wide range of physiological and patho-physiological mechanisms. In particular, 5-HT1A receptors are proposed to mediate stress-adaptation. The aim of this research was to investigate in adolescent rats: first, the consequences of perinatal exposure to 5-metoxytryptamine (5MT), a 5-HT1/5-HT2 serotonergic agonist, on behavioural-stress reactivity in elevated plus maze, open field and forced swim tests; secondly, whether the behavioural effects induced by perinatal exposure to 5MT on open field and forced swim tests were affected by the selective 5-HT1A receptor agonist LY 228729, a compound able to elicit a characteristic set of motor behaviours on these experimental models, and by the co-administration of the selective and silent 5-HT1A antagonist WAY 100635. Results indicate that a single daily injection of 5MT to, pregnant dams from gestational days 12 to 21 (1mg/kg s.c.), and to the pups from postnatal days 2 to 18 (0.5mg kg s.c.), induce in the adolescent rat offspring: an increase in the percentage of entries and time spent on the open arms in the elevated plus maze; a reduction in locomotor activity and rearing frequency, and an increase in the time spent on the central areas in the open field test; a decrease in immobility and an increase in swimming in the forced swim test. Acute administration of LY 228729 (1.5mg/kg s.c.) strongly decreases rearing frequency and increases peripheral activity in the open field test, and decreases immobility and increases swimming in the forced swim test both in perinatally vehicle and 5MT-exposed offspring. Co-administration of WAY 100635 (0.25mg/kg s.c.) abolishes the effects exerted by LY 228729. These results suggest that, in the adolescent rat, perinatal exposure to 5MT enhances the stress-related adaptive behavioural responses, presumably through a predominant action on presynaptic 5-HT1A receptors and does not deteriorate the functional response of 5-HT1A receptors to selective agonist and antagonist compounds.

Reversal of prenatal diazepam-induced deficit in a spatial-object learning task by brief, periodic maternal separation in adult rats.

In the rat, prenatal exposure to diazepam (DZ) induces a permanent reduction in GABA/BZ receptor (R) function and behavioural abnormalities. Environmental modifications during early stages of life can influence brain development and induce neurobiological and behavioural changes throughout adulthood. Indeed, a subtle, periodic, postnatal manipulation increases GABA/BZ R activity and produces facilitatory effects on neuroendocrine and behavioural responses. We here investigated the impact of prenatal treatment with DZ on learning performance in adult 3- and 8-month-old male rats and the influence of a brief, periodic maternal separation on the effects exerted by prenatal DZ exposure. Learning performance was examined employing a non-aversive spatial, visual and/or tactile task, the "Can test". Behavioural reactivity, emotional state and fear/anxiety-driven behaviour were also examined using open field (OF), acoustic startle reflex (ASR) and elevated plus-maze (EPM) tests. A single daily injection of DZ (1.5mg/kg, s.c.), over gestational days (GD) 14-20, induced, in an age-independent manner, a severe deficit in learning performance, a decrease in locomotor and explorative activity and an increase in peak amplitude in the ASR. Furthermore, anxiety-driven behaviour in EPM was disrupted. Daily maternal separation for 15 min over postnatal days 2-21 exerted opposite effects in all the paradigms examined. Prenatally DZ-exposed maternal separated rats, in contrast to respective non-separated rats, showed an improvement in learning performance, a decrease in emotionality and a normalization of the exploratory behaviour in EPM. These results suggest that a greater maternal care, induced by separation, can serve as a source for the developing brain to enhance neuronal plasticity and to prevent the behavioural abnormalities induced by prenatal DZ exposure.

Antimicrobial and antiproliferative activity of Peucedanum nebrodense (Guss.) Strohl.

Acetone extract of Peucedanum nebrodense (Guss.) Strohl., a rare endemic species from the Madonie mountains (Sicily), was tested in vitro for its antimicrobial activity against bacterial reference strains and antiproliferative activity against K562 (human chronic myelogenous leukemia), HL-60 (human leukemia) and L1210 (murine leukemia) cell lines. The acetone extract showed antiproliferative IC50 values in the range of 14-0.27 microg/ml.

Phenylamides of 1-phenyl (or methyl)-5-benzamidopyrazole-4-carboxylic acid as vratizolin analogs with analgesic and antiinflammatory activities.

A number of phenylamides of 5-benzamidopyrazole-4-carboxylic acid were prepared in 50-80% yields from 1-phenyl (or methyl)-6-phenylpyrazolo[3,4-d]1,3-oxazin-4(1H)-ones and aniline derivatives. All the compounds were tested for their analgesic and antiinflammatory activities, as well as for their ulcerogenic potential and acute toxicity. Some derivatives, when compared to phenylbutazone, proved more active in the tests for analgesic and antiexudative activities, but less active in the carrageenin paw oedema test. The compounds proved to posses marginal or no ulcerogenic effect, as well as low systemic toxicity.

Synthesis and antiproliferative activity of novel 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives.

Several new 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives 5 and 6 were synthesized and tested for their in vitro antiproliferative activity against Raji, K562, and K562-R cell lines. The pharmacological screening showed that some 2, 6, or 7-substituted quinazolinones 5 posses a significant antiproliferative activity, with a percentage growth inhibition ranging from 44.8% to 100% at 50 microM, which was higher than that showed by the unsubstituted derivative 5a previously synthesized. For the most active compounds 5d, 5f, and 5g the IC50 were recorded.

Synthesis of new 3-(3-phenyl-isoxazol-5-yl) or 3-[(3-phenyl-isoxazol-5-yl)-amino] substituted 4(3H)-quinazolinone derivatives with antineoplastic activity.

A novel series of 3-(3-phenyl-isoxazol-5-yl) or 3-[(3-phenyl-isoxazol-5-yl)amino] substituted 4(3H)-quinazolinone derivatives was synthesized. The compounds were tested for their antineoplastic activity in vitro against Raji (human Burkitt limphoma). K-562 (human chronic myelogeneous leukemia) and U937 (human histiocytic limphoma) cell lines. The most active quinazolinones showed IC50 values in the range 16-30 microM.

Synthesis and antifungal activity of new N-isoxazolyl-2-iodobenzamides.

N-Isoxazolyl-2-iodobenzamides 3 and 9, with a benodanil-like structure, were synthesized by refluxing in acetic acid the corresponding benzotriazinones 2 and 8 with potassium iodide for 1 h with the aim to ascertain if they were active as fungicides against Phytophthora citricola Saw., Botrytis cinerea Pers., Rhizoctonia sp. and Alternaria sp. Among the tested iodo derivatives, compounds 3b and 9a possess interesting activities against the aforesaid fungal strains in several cases similar to that of benodanil I taken as reference drug.

Synthesis and pharmacological activities of novel 3-(isoxazol-3-yl)-quinazolin-4(3H)-one derivatives.

Several new 3-(isoxazol-3-yl)-quinazolin-4(3H)-one derivatives were synthesized and tested for their analgesic and antiinflammatory activities, as well as for their acute toxicity and ulcerogenic effect. A few compounds were as active as phenylbutazone in the writhing and acetic acid peritonitis tests. They had a very low ulcerogenic effect.

Nephrotoxicity of halogenated vinyl cysteine compounds.

S-(1,2-dichlorovinyl) cysteine (DCVC), is a potent nephrotoxin. In order to determine if other vinyl cysteine conjugates were nephrotoxic, halogenated vinyl cysteines, HVC-1 and HVC-2, were prepared from chlorotrifluoroethylene (CTFE), a fluorocarbon monomer, or chlorotifluoroethylene, a metabolite of halothane, respectively. Three days after receiving DCVC (5-10 mg/kg), CD-1 mice developed focal renal tubular necrosis. Mice treated with HVC-1 or HVC-2 (5-10 mg/kg) also developed renal necrosis by 3 days post exposure. HVC-1 was not as potent as DCVC with the necrosis limited to the pars recta. At equivalent doses HVC-2 caused less necrosis of the pars recta than HVC-1. The degree of nephrotoxicity by all three compounds exhibited a dose-response from 1-25 mg/kg. Doses greater than 25 mg/kg were often lethal within 3 days and the mice had a complete zonal necrosis of the renal cortex and a two-fold increase in kidney weight. Structural analogues, S-(chlorethyl) or S-(hydroxyethyl) cysteine, did not cause renal necrosis in mice at doses up to 200 mg/kg. These studies indicate that the enzymes reportedly responsible for converting DCVC to a nephrotoxic intermediate will also bioactivate other halogenated vinyl cysteines.