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.

Synthesis and biological activity of new anti-inflammatory compounds containing the 1,4-benzodioxine and/or pyrrole system.

A series of substituted derivatives containing the 1,4-benzodioxine or pyrrole nucleus are described. All the newly synthesized compounds were examined for their in vitro and in vivo anti-inflammatory activity. Several derivatives, including (S)-2, 14 and 17, showed more anti-inflammatory activity in vivo in these assays (rat paw oedema induced by carrageenan) than the known classical anti-inflammatory agent ibuprofen, whereas other compounds like 1 were equipotent to ibuprofen. Compound 17 was the most outstanding derivative because of its remarkable in vivo anti-inflammatory activity. In this paper, we examine and discuss the structure-activity relationships and anti-inflammatory activities of these compounds.

[Census 2004 of the Italian nephrology and dialysis units. Campania, Sicilia and Sardegna]. / Censimento 2004 dei Centri di Nefrologia e Dialisi Italiani. Campania - Sicilia - Sardegna.

This paper completes the 2004 national survey of Renal and Dialysis Units organised by the Italian Society of Nephrology (SIN), and presents data from the last three Italian Regions, Campania, Sicilia and Sardegna. The major purpose of this initiative was to obtain a benchmark reference on national and regional basis. Main findings in the 3 Regions, respectively: A) STRUCTURAL RESOURCES: Renal Units = 28, 30, 19; Private Dialysis Units = 126, 95, 4; total Renal and Dialysis Units 27, 26, 21 pmp (per million population); % of private facilities = 81, 74, 12%; hospitalization beds = 35, 40, 32 pmp; dialysis stations = 337, 356, 265 pmp. B) PERSONNEL RESOURCES: physicians = 88, 75, 67 pmp; dialysis nurses = 162, 136, 247 pmp; each physician treats 10, 12, 12 dialysis patients and each dialysis nurse treats 4.7, 4.0, 3.3 dialysis patients. C). ACTIVITY: hospitalizations = 1334, 1911, 1851 pmp; renal biopsies = 50, 66, 100 pmp. D). EPIDEMIOLOGY: prevalence of dialysis patients = 842, 915, 822 pmp; prevalence of transplanted patients = 269, 212, 327 pmp; incidence of dialysis patients = 187, 199, 150 pmp; gross mortality rate of dialysis patients = 12.9%, 12.1%, 12.5%; distribution of vascular accesses in prevalent dialysis patients: arteriovenous fistulas = 93%, 84%, 77%; central venous catheters = 6%, 12%, 15%,; vascular grafts = 1%, 3%, 8%. Compared to other Regions, Campania and Sicilia have an abnormal high rate of private Dialysis Units, resulting in difficulties in optimizing structural and economic resources. Furthermore, the independence of some of these structures from a Renal Unit interferes with an adequate treatment of dialysis patients.

Synthesis and antimicrobial evaluation of new phenoxyacetamide derivatives.

New N-(5-methylisoxazol-3-yl)-2 or 3 or 4-(phenoxyacetamido)benzamides 6a-t were synthesized and tested for their in vitro antimicrobial activity against gram positive (Staphylococcus aureus ATCC 25923) and gram negative (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853) bacteria as well as fungi (Candida albicans ATCC 10231, Candida tropicalis ATCC 13803 and Cryptococcus neoformans ATCC 90112). Compounds 6 were devoid of antibacterial as well as antifungal activities at maximum tested concentrations of 50 micrograms/ml for bacteria and 100 micrograms/ml for yeast.

Synthesis and pharmacological study of ethyl 1-methyl-5-(substituted 3,4-dihydro-4-oxoquinazolin-3-yl)-1H-pyrazole-4-acetates.

Several new ethyl 1-methyl-5-(substituted 3,4-dihydro-4-oxoquinazolin-3-yl)-1H-pyrazole-4-acetates 2, substituted at 2 and, alternatively at, 6, 7 or 8 positions of the quinazolinone nucleus, were synthesised. The compounds were screened for their analgesic and antiinflammatory activities, acute toxicity and ulcerogenic effect. Substitution in the benzene moiety of the quinazolinone ring did not show any advantage for the analgesic activity, whereas it improved in some cases the antiinflammatory activity. Some compounds showed appreciable antiinflammatory activity and, at the same time, very low ulcerogenic index.

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.

Hypocomplementemic type II membranoproliferative glomerulonephritis in a male patient with familial lecithin-cholesterol acyltransferase deficiency due to two different allelic mutations.

Patients with familial lecithin-cholesterol acyltransferase (LCAT) deficiency very often show progressive glomerulosclerosis with evolution to end-stage disease. High levels of an abnormal lipoprotein (lipoprotein X) cause glomerular capillary endothelial damage. The ultrastructural study of renal biopsy specimens shows characteristic glomerular deposits of membrane-like, cross-striated structures and vacuole structures. The gene encoding for LCAT has been mapped to chromosome 16q22.1, and several mutations of this gene cause LCAT deficiency which is inherited as an autosomal recessive trait and which is characterized by corneal opacities, normochromic normocytic anemia, and renal dysfunction. Herein we report clinical features and renal histological findings concerning a 24-year-old male patient with classical familial LCAT deficiency due to two different allelic mutations: a nonsense mutation inherited from the father and a missense mutation inherited from the mother. Moreover, the patient showed glomerular histological lesions and an immunofluorescent glomerular pattern typical of hypocomplementemic membranoproliferative type II glomerulonephritis (dense-deposit disease). The nature of electron-dense material that characterizes dense-deposit disease is still unknown, but there are suggestions that some chemical modifications might occur in the renal basement membranes. Therefore, this clinical case might induce to consider possible relations between disorders of the lipoprotein metabolism and renal dense-deposit disease.

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 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 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 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.

Synthesis and pharmacological evaluation of 1-methyl-5-[substituted-4 (3H)-oxo-1,2,3-benzotriazin-3-yl]-1H-pyrazole-4-acetic acid derivatives.

Several new 1-methyl-5-[substituted-4-oxo-1,2,3-benzotriazin-3-yl] -1H-pyrazole-4-acetic acids and their ethyl ester derivatives were prepared. The compounds were tested for analgesic and antiinflammatory activities, acute toxicity, ulcerogenic effect, and as in vitro inhibitors of 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), since it is claimed that the inhibition of such an enzyme predicts in vivo antiinflammatory activity. Some compounds were more active than phenylbutazone in the phenylbenzoquinone and acetic acid peritonitis tests, and equiactive to the same drug in the carrageenin paw edema test. All the compounds inhibited the 3 alpha-HSD, but no correlation was observed with the paw edema inhibition values. The compounds proved to possess marginal or no ulcerogenic effect, as well as low systemic toxicity.

Synthesis and antineoplastic activity of new 4-diazopyrazole derivatives.

Several new 4-diazopyrazole derivatives were synthesized by reaction of 1-(R-substituted)phenyl-3-methyl-5-benzamidopyrazoles with a sevenfold excess of nitrous acid in acetic media. The compounds were tested at 20 microM concentration for their antineoplastic activity in vitro against Raji (human Burkitt lymphoma), K562 (human chronic myelogenous leukemia) and U937 (human histiocytic lymphoma) cell lines. They showed a percent of growth inhibition in the range 23.4-100%.

Synthesis of new 2-([(phenoxy or phenyl)acetyl]amino)benzoic acid derivatives as 3 alpha-hydroxysteroid dehydrogenase inhibitors and potential antiinflammatory agents.

A number of 2-([(phenoxy or phenyl)acetyl]amino)benzoic acid derivatives were prepared in about 50% yield from (phenoxy or phenyl)acetyl chloride and anthranilic acid derivatives. All the compounds were tested as in vitro inhibitors of 3 alpha-hydroxysteroid dehydrogenase, since enzyme inhibition predicts potential antiinflammatory activity in vivo. The most active compounds 3 l, m, s are about 3.5 times more active than acetylsalicylic acid (ASA). Activity is influenced by electronic as well as steric effects.

3 alpha-hydroxysteroid dehydrogenase inhibitory activity of some N(3)-(1-R-4-carboxypyrazol-5-yl)-1,2,3-benzotriazin-4(3H)-one and quinazolin-4(3H)-one acids.

Some carboxylic acids of N(3)-pyrazole substituted 1,2,3-benzotriazin-4-(3H)-ones and- quinazolin-4-(3H)-ones were prepared and tested for the inhibitory property of 3 alpha-hydroxysteroid dehydrogenase of rat liver cytosol. The results indicated that the degree of inhibition can be used to predict the antiinflammatory potency of the compounds described.

Synthesis and pharmacological study of some 3-(isoxazol-5-yl)-quinazolin-4(3H)-ones.

A number of new 3-(isoxazol-5-yl)-quinazolin-4(3H)-ones was prepared and tested, together a few analogues previously obtained, for their analgesic, antipyretic and antiinflammatory activities, as well as for their acute toxicity and ulcerogenic effects. In the carrageenan rat foot edema model one of the tested compounds showed activity and LD50 comparable to that of ASA, but the ulceration index approximated zero value.

Synthesis and evaluation of antimicrobial activity of new 4-nitroso and 4-diazopyrazole derivatives.

Some N-(pyrazol-5-yl)-2-nitrobenzamides, variably substituted in the pyrazole nucleus as well as in the amidic group, were reacted in acetic acid media with potassium nitrite and hydrochloric acid. The different chemical behaviour of the reacted pyrazole derivatives in relation to the substitution pattern in both the pyrazole nucleus and the amidic group, was observed. All compounds isolated from the reaction mixtures (4-nitroso, 4-nitro, 4-diazo and 4-chloro derivatives) were evaluated by the agar diffusion method for their "in vitro" growth inhibitory activity against Candida albicans (our collection), Candida tropicalis ATCC 13803, Saccharomyces cerevisiae ATCC 36375, Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853. The 1-methylpyrazole derivatives showed larger inhibition zones than the 1-phenyl ones in the antimicrobial tests.

Antiinflammatory pyrazolones and pyrazolidones: a study of their inhibition of 5 beta-dihydrocortisone reduction in rat liver cytosol.

Seven pyrazolone and pyrazolidone derivates, some of them widely used as analgesic and anti-inflammatory drugs, were tested for the inhibitory property of the 3 alpha-hydroxysteroid dehydrogenase of rat liver cytosol. The data obtained clearly show that, among pyrazolone and pyrazolidone derivates, the correlation between IC50 and therapeutic potency is not always verified.