Synthesis and prostaglandin-like activity of 2-(trans-3-hydroxy-1-octenyl)-3-indoleheptanoic acid.

The synthesis of 2-(trans-3-hydroxy-1-octenyl)-3-indoleheptanoic acid (1) is described. The title compound appeared to show a weak prostaglandin-like activity in two different systems. It contracted rat stomach fundus strips and guinea-pig ileum preparations only at concentrations about 10(3)- and 10(2)-fold higher, respectively, than PGE1. Moreover, it stimulated adenylate cyclase from rat liver plasma membrane, but the relative potency was 4--5 X 10(2)-fold lower than the natural compound. The title compound showed also a certain degree of PGE1 antagonism.

6-Alkyl and 6-arylcarbamoyloximino pyrazolo[3,4-b][1,4]diazepines as potential fungicidal, insecticidal and herbicidal agents.

A series of 6-alkyl and 6-arylcarbamoyloximinopyrazolo[3,4-b][1,4]diazepines was prepared and evaluated for fungicidal, insecticidal and herbicidal activity. No one compound showed a general effect but individual compounds exhibited specific activities.

Pyrazolo[3,4-d][1,2,3]triazole-1-carboxamides and 5-alkylaminopyrazolo[3,4-d]oxazoles: synthesis and evaluation of the in vitro antifungal activity.

A series of N-alkyl-N'-(4-diazo-5-pyrazolyl)-ureas (4) was thermally and photochemically converted into pyrazolo [3,4-d][1,2,3]triazole derivatives (5,6) and 5-alkylaminopyrazolo[3,4-d]oxazoles (7) respectively. The products were tested for in vitro antifungal activity against Fusarium culmorum, Botrytis cinerea, Phoma betae, Pythium ultimum, Sclerotinia minor and Rhizoctonia solani. The MIC and ED50 values of compound (6) against some of the test fungi were comparable to those of the reference fungicides iprodione and mancozeb.

4-Diazo-5-alkylsulphonamidopyrazoles: synthesis and evaluation of biological activity.

A series of 4-diazo-5-alkylsulphonamidopyrazoles (5) was prepared and tested for antitumor, antiviral and antimicrobial activity. Compounds (5a) and (5b) showed a selective, although not very potent cytostatic activity against L1210 and a human T lymphoblastoid cell line (C8166). Compounds (5a) and (5d-h) showed a selective anti-coxsackie B1 virus activity, whereas 5b was also endowed with some activity against Bacillus subtilis.

[Epidemiological, social and public health aspects of tuberculosis in Ferrara in the 19th century]. / Aspetti epidemiologicie socio-sanitari dellatubercolosi a Ferrara nell'800.

Our first study of tuberculosis in Ferrara during the nineteenth century, whose results have been recently published, focused on disease treatment. Here we present the descriptive analysis of mortality, with the following results being attained: two behavioural patterns are detected with regard to the onset of disease, before and after 1850; TB is a specific disease that affects all parts of the body in all age groups: childhood, and active and passive populations; there are no significant differences with regard to gender; as regards the occupations performed by the deceased, those related to industry and agriculture and to various other activities and services are those with the highest mortality; tuberculosis has a seasonal pattern; summer and autumn are the periods of greatest prevalence (hot weather and humidity are factors that affect the respiratory system); among the forms of tuberculosis it can be observed that up to the year 1850 people died in Ferrara either of pulmonary tuberculosis or TB localised in other areas; from 1851 onward there appears to have been a dramatic change, with a decrease in unspecific diagnosis but the appearance of disease manifestations in its various clinical forms.

Emerging antifungal azoles and effects on Magnaporthe grisea.

Derivatives of pyrazolo[1,5-a][1, 3, 5]triazine-2,4-dione,pyrazolo[1,5-c][1, 3, 5]thiadiazine-2-one, pyrazolo[3,4-d][1, 3]thiazine-4-one, and pyrazolo[3,4-d][1, 3]thiazine-4-thione were screened for antifungal activity against the causal agent of rice blast disease, Magnaporthe grisea. The compounds were tested at doses ranging from 10 to 200mugml(-1), using the commercial fungicide tricyclazole as reference compound. All triazine derivatives inhibited the growth and pigmentation of the mycelia less effectively than tricyclazole. The thiadiazine derivatives proved to be more effective than their triazine counterparts, but only 4-(butylimino)-7-methylpyrazolo[1,5-c][1,3,5]thiadiazine-2-one (2h) and 4-(cyclohexylimino)-7-methylpyrazolo[1,5-c][1,3,5]thiadiazine-2-one (2j) were more effective than tricyclazole. Pyrazolo[3,4-d][1,3]thiazine-4-one derivatives were active only at the highest doses, whereas members of the pyrazolo[3,4-d][1,3]thiazine-4-thione series inhibited fungal growth at the lowest concentrations used, at which tricyclazole had no effect. A dose-dependent mechanism might be responsible for this effect, with lipophilicity as the governing factor. Within a given set, the presence of a cyclohexyl or an n-butyl group generally increased antifungal activity, with respect to both growth inhibition and cell de-pigmentation of the mycelium, suggesting that a higher lipophilicity might improve transport inside the cells. SEM and TEM of M. grisea hyphae showed that treatment with the most active substance (2h) caused significant ultrastructural effects, particularly on the endomembrane system, suggesting a mechanism of action similar to that of most azole fungicides. Dissimilarities were also observed, with no alterations of the cell wall evident. In conclusion, several compounds showed greater inhibition than tricyclazole, and therefore provide useful new chemistry for control of M. grisea infections.

Chemical characterization and antifungal activity of essential oil of capitula from wild Indian Tagetes patula L.

The essential oil extracted by steam distillation from the capitula of Indian Tagetes patula, Asteraceae, was evaluated for its antifungal properties and analyzed by gas chromatography and gas chromatography-mass spectrometry. Thirty compounds were identified, representing 89.1% of the total detected. The main components were piperitone (24.74%), piperitenone (22.93%), terpinolene (7.8%), dihydro tagetone (4.91%), cis-tagetone (4.62%), limonene (4.52%), and allo-ocimene (3.66%). The oil exerted a good antifungal activity against two phytopathogenic fungi, Botrytis cinerea and Penicillium digitatum, providing complete growth inhibition at 10 microl/ml and 1.25 microl/ml, respectively. The contribution of the two main compounds, piperitone and piperitenone, to the antifungal efficacy was also evaluated and ultrastructural modifications in mycelia were observed via electron microscopy, evidencing large alterations in hyphal morphology and a multisite mechanism of action.

Antifungal effects of the 3-methyl-5-aminoisoxazole-4-thiocyanate on some dermatophytes.

This preliminary research demonstrates the dose dependent antimycotic effect of 3-methyl-5-aminoisoxazole-4-thiocyanate against a number of animal and human dermatophytes. The in vitro results suggest potential medical applications.

Carboxyl activation in peptide synthesis using 4-oximino-pyrazol-5-ones.

4-Oximino-pyrazol-5-ones 2a, b and their esters with N-protected amino acids 3a, b have been studied for carboxyl activation in peptide synthesis. 2a, b and 3a, b appear to be diastereoisomeric mixtures whose configurations have been assigned on the basis of spectroscopic and X-ray data. Some peptides obtained using these pyrazolone derivatives are reported: no racemization was noted by the Weigand test.

[Synthesis of compounds with antisecretory activity]. / Sintesi di composti ad attività antisecretoria.

Some indole and pyrrolidone derivatives of two peptides, H-Ile-His-Pro-NH2 and N epsilon-Boc-Lys-Ile-His-Pro-NH2, were prepared and tested for antisecretory activity. A report is given of the synthetic scheme used for the two peptides which is a modified Jones procedure, the preparation of pyrrolidin-5-one-N-heptanoic acid and 1H-indol-3-heptanoic acid, the introduction on the peptide chain of indole and pyrrolidone radicals and the results of the pharmacological investigation.

Synthesis of a novel series of imidazo[4,5-c]pyrazole derivatives and their evaluation as herbicidal agents.

Ever changing problems in agricultural weed control require periodic introduction of new herbicides. Imidazo[4,5-c]pyrazoles, which were considered of interest as potential herbicides, were synthesized and examined for the pre-emergence, post-emergence, and post-transplant control of weeds in rice against broadleaf and grass weed species. The data obtained suggest that some imidazo[4,5-c]pyrazoles have potential herbicidal activity against a wide range of weeds, with 5-methyl, 5-thiomethyl, and 5-unsubstituted derivatives being the most effective. No herbicidal activity was observed in the 5-methylsulfonylimidazo[4,5-c]pyrazole and imidazo[4,5-c]pyrazolone series.

Morphological study of Trichophyton rubrum: ultrastructural findings after treatment with 4-amino-3-methyl-1-phenylpyrazolo-(3,4-c)isothiazole.

The antifungal activity of 4-amino-3-methyl-1-phenylpyrazolo-(3,4-c)isothiazole was studied on Trichophyton rubrum. The compound, at concentrations between 20 and 10 microg ml(-1), induces a remarkable reduction in the growth and causes deep morphogenetic anomalies. The ultrastructural modifications have demonstrated that the compound targets the cell membrane of the fungus, breaking down not only the endomembrane system, but also the 'outer' membrane, with consequent extrusion of materials in the medium. The results suggests a mechanism of action similar to other azoles clinically utilized.

Antifungal screening of seven new azole derivatives.

Two strains of the dermatophyte Epidermophyton floccosum were treated with seven new synthetic azole derivatives to determine their possible antifungal activity. Among these, two diazopyrazoles (1-phenyl-3-methyl-4-diazo-5-methanesulphonamid and 1,3-dimethyl-4-diazo-5-methanesulphonamid) and the triazole (4-methyl-6-t-butylpyrazolo[3,4-d] [1,2,3]triazole) were inactive at the highest dose tested (100 micrograms/ml). The 4-methyl-6-phenyl-pyrazolo[3,4-d] [1,2,3]triazole produced only a partial inhibition of growth, whereas the most active compounds were the two thiadiazines (6H-3-phenyl-5-methyl-7-(3,4-dichlorophenyl)pyrazolo[3,4-c] [1,2,5]thiadiazine-2,2-dioxide and 7-methyl-2-phenyl-4H-pyrazolo[1,5-c] [1,3,5]thiadiazine-4-one), and an aminoisoxazole (3-methyl-5-aminoisoxazole-4-thiocyanate), which induced a remarkable and sometimes complete reduction in the growth rate of the fungus. The structure-activity relationships are discussed.

Antifungal activity of 5 new synthetic compounds vs. Trichophyton rubrum and Epidermophyton floccosum.

The antifungal activity of five new synthetic compounds was evaluated on two dermatophytes: Epidermophyton floccosum and Trichophyton rubrum. The data showed that the imidazo-pyrazole and pyrazolo-thiazoles were not particularly effective, while the two pyrazole-thiocyanates proved highly active on both fungi. The most active 5-amino-3-methyl-1-phenylpyrazolo-4-thiocyanate was chosen to perform SEM and TEM morphological studies on both fungi. Both SEM and TEM observations revealed interesting alterations on the two dermatophytes, particularly involving the endomembrane system.

Mannan changes induced by 3-methyl-5-aminoisoxazole-4-thiocyanate, a new azole derivative, on Epidermophyton floccosum.

The antifungal activity of 3-methyl-5-aminoisoxazole-4-thiocyanate, a new azole derivative, was studied on the dermatophyte Epidermophyton floccosum. The compound strongly inhibited the in vitro growth of two different strains of the fungus and even induced profound morphogenetic anomalies. Optical and electron microscopy showed that such treatment targets the endomembrane system, particularly the plasmalemma, causing abnormal extrusion of the wall mannans. This results in improper arrangement of the different parietal materials; the walls are thus weak and subject to subapical rupture which terminates cell growth and elongation of the hypha. The morphological results and the preliminary biochemical data on fungal sterols suggest that this compound employs an action mechanism similar to that of other azoles used in therapy.

[Synthesis of pyrazole and pyrazolo [4,3-d] pyrimidinone derivatives. II]. / Sintesi di derivati pirazolici e pirazolo [4,3-d] pirimidinonici. Nota II.

Three new series of pyrazolic and pyrazolo-pyrimidinonic derivatives (II a-g), (III a-g) and (IV a-g), containing the substituted phenyl-hydrazide moiety were prepared and studied in order to check some information on the analgesic and antipyretic activity of an analogous series obtained in a previous work. Some derivatives (II b), (II d), (II f), (III b), (III c) and (IV d) show interesting analgesic activity.

[Synthesis of pyrazole derivatives and pyrazolo[4,3-d]pyrimidines. I]. / Sintesi di derivati pirazolici e pirazolo[4,3-d]pirimidinonici. Nota I.

Three series of pyrazole derivatives (III a-g), (IV a-g) and (V a-g) were synthesized and tested for analgesic, antipyretic and antiinflammatory activity. Many of tested compounds showed interesting analgesic and antipyretic activity, whereas no compounds exhibited any antiinflammatory activity.

Synthesis and antifungal activity of 4-thiazol-2-yl-5-aminopyrazoles and 4-aminopyrazolo [3,4-c] isothiazoles.

Starting from 4-thiocarbamoyl-5-aminopyrazoles (I), the AA could prepare two series of products: 4-thiazol-2-yl-5-aminopyrazoles (II) and 4-aminopyrazolo [3,4-c] isothiazoles (III). The screening for in vitro antifungal activity evidenced that compounds (III) are effective in controlling most examined fungi; in particular 1-phenyl-3-methyl-4-aminopyrazolo [3,4-c] isothiazole (III a) at the concentration of 20 p.p.m. completely inhibited the growth of Pythium ultimum and Corticium solani, responsible for the collar rot of the beet.

Alterations in spore production in Trichophyton rubrum treated in vitro with 1-amino-6-methyl-4-phenylpyrazolo[3,4-d]-1,2,3-triazole.

The effects of the newly synthesized triazole, 1-amino-6-methyl-4-phenylpyrazolo[3,4-d]-1,2,3-triazole (V5), on the dermatophyte Trichophyton rubrum were tested. Optical and electron microscopy showed that the treatment suppressed the various forms of saprophytic conidia, induced the formation of chlamydospores and accelerated the formation of arthroconidia. This new triazole did not reveal any fungistatic or fungicidal activity and could not be considered as an antifungal substance.

Synthesis and biological evaluation of a series of substituted pyrazolo[3,4-d]-1,2,3-triazoles and pyrazolo[3,4-d]oxazoles.

In view of the biological relevance of triazole-based heterocyclic structures as antifungal, antiviral, and antitumor agents, we have synthesized a series of substituted pyrazolo[3,4-d]-1,2,3-triazoles (2e-h, 2j, 4b) which we evaluated for their cytostatic and antiviral (HIV-1 included) activity and for their capability to inhibit the multiplication of various human pathogenic fungi and bacteria. Moreover, the biological activities of a few compounds, namely pyrazolo[3,4-d]oxazoles (3a-e) and pyrazolo[3,4-d]-1,2,3-triazoles (2a-d, 4a, 5), previously obtained by us but not investigated for their biological activity, were also studied. Only compounds 3a-e were endowed with a significative antiproliferative activity on the human lymphoblastoid cell line MT-4 cells. All pyrazole derivatives proved ineffective in protecting cell cultures against the HIV-1-induced cytopathogenicity, and none of the compounds was active against the bacteria and fungi tested.