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Melanins are very important pigments for the survival and longevity of fungi, so their biosynthesis inhibition is a new biochemical target aiming at the discovery of selective fungicides. In this work is described the synthesis of new pyrazolo-thiazolo-triazole compounds, analogues of tricyclazole (a commercial antifungal product that acts by inhibiting melanin synthesis), and their biological activity was studied on some dermatophytes and phytopathogens. The compounds poorly inhibited the growth and pigmentation of fungi tested and were less efficient than tricyclazole. Electron microscopy on Botrytis cinerea showed that treatment with the most active compound caused abnormally thickened and stratified walls in fungi, whose ultrastructure was, in contrast, generally normal. The fungus treated with tricyclazole, on the other hand, appeared to be drastically altered, so as to become completely disorganized. These results suggest that the new azole compounds employ an action mechanism similar to that of other azoles, but dissimilar to that of tricyclazole.

Some pyrazolo[3,4-d]pyrimidin-4(5H)-thione, pyrazolo[3,4-d][1,3]thiazin-4-one/thione, and pyrazolo[1,5-c][1,3,5]thiadiazine-4-one/thione derivatives were synthesized and screened for antifungal activity against the causal agent of rice blast disease, Magnaporthe grisea. In all cases a remarkable inhibition of fungal growth was found in the range from 10 to 200 μg mL-1. Several compounds were able to control mycelium growth at a rate of 10 μg mL-1, a concentration at which the reference compound tricyclazole was completely ineffective. At least in the case of the most active substance, at the same dose the growth of seedlings or cultured cells of rice was substantially unaffected. Results allowed definition of structural requirements either to maintain or to enhance mycotoxic activity. Keywords: Rice; blast; Magnaporthe grisea; antifungals; pyrazolo[3,4-d][1,3]thiazine; pyrazolo[1,5-c][1,3,5]thiadiazine; pyrazolo[3,4-d]pyrimidine

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.

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.

Thiation of N-(1-tert-butyl-3-methylpyrazol-5-yl)carboxamides 2 with the Lawesson reagent afforded the corresponding thiocarboxamides 3. Heating of 3 in formic acid gave the N-dealkylated thiocarboxamides 4 which were cyclized into 4H-pyrazolo[1,5-c][1,3,5]thiadiazine-4-thiones 5 by treatment with thiophosgene.

An efficient synthesis of pyrazolo[3,4-d]thiazoles (6) was achieved by treatment of N-(4-amino-5-pyrazolyl)thiocarboxamides (4) with sodium nitrite in acidic medium followed by irradiation with uv light

Trichloromethyl chloroformate reacts with N-(1-alkyl/aryl-5-pyrazolyl) thiocarboxamides (2a-j) to give pyrazolo[3,4-d][1,3]thiazin-4-ones (3) while it reacts with N-(3-methyl-5-pyrazolyl)thiobenzamide (2m) to give the pyrazolo[1,5-c] [1,3,5]thiadiazine-4-one (4). Heating under reflux in formic acid of homologues (3g-i) bearing a tert-butyl group linked to pyrazole N-1 atom afforded the dealkylated derivatives (3k-m)

Thiation of N-(1-tert-butyl-3-methylpyrazol-5-yl)carboxamides 2 with the Lawesson reagent afforded the corresponding thiocarboxamides 3. Heating of 3 in formic acid gave the N-dealkylated thiocarboxamides 4 which were cyclized into 4H-pyrazolo[1,5-c][1,3,5]thiadiazine-4-thiones 5 by treatment with thiophosgene.

The syntheses of 4-, 5-, and 6- substituted imidazo[4,5-c]pyrazoles, compounds of potential biological activity, are reported.

The synthesis of imidazo[4,5-c]pyrazol-5-ones (6) is reported. 5-Amino-4-ethoxycarbonylaminopyra-zoles 3a-g when heated at 200° for 2 hours afford 6a-g. In a similar manner imidazo[4,5-c]pyrazol-5-one (6a) is readily obtained from 4-amino-5-ethoxycarbonylaminopyrazole (5a).

Condensation of pyrazolyl isothiocyanates 2 with N-substituted hydrazines provided the 2-methyl/phenyl-4-(pyrazol-5-yl)thiosemicarbazides 3. Cyclization of 3 with formic acid-acetic anhydride or with triethyl orthoacetate-acetic anhydride provided 4-(pyrazol-5-yl)-l,2,4-triazole-3-thiones 4a-f and 5-methyl-4-(pyrazol-5-yl)-1,2,4-triazole-3-thiones 4g-I respectively.

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.

Ethyl 2-amino-3-methoxycarbonyl-4-oxo-2-pentenoate (3) reacts with hydroxylamine or hydrazines to give isoxazole and pyrazole ortho-dicarboxylic acid esters 4 and 5, respectively. Partial hydrolysis of diesters 4 and 5 afforded the corresponding dicarboxylic acid monoesters 6 and 7. Amidation of the intermediate acid chlorides 8,9 followed by hydrolysis of 4-methylesters 10, 11 gave the title compounds 1 and 2, respectively.

Two series of new pyrazoles, namely six pyrazolo[1,5-a][1,3,5]triazine-2,4-dione and four pyrazolo[1,5-c][1,3,5]thiadiazine-2-one derivatives, were synthesized as potential inhibitors of the photosynthetic electron transport chain at the photosystem II level. The compounds were confirmed by 1H NMR, elemental, and IR analyses. Their biological activity was evaluated in vivo upon both the growth of blue-green algae and the photosynthetic oxygen evolution by eukaryotic algae and in vitro as the ability to interfere with light-driven reduction of ferricyanide by isolated spinach chloroplasts. Some compounds exhibited remarkable inhibitory properties, comparable to those of the reference commercial herbicides lenacil, diuron, and hexazinone. Results suggest that the substitution of triazine with thiadiazine ring may act as amplifier for herbicidal activity. Keywords: Herbicides; photosynthetic electron transport inhibitors; photosystem II

We investigated the activity of a pyrazolo-isothiazole derivative (G8) against Cryptococcus neoformans. A first screening test showed that G8 at 10 mg/L inhibited the growth of 14 of 15 clinical isolates tested. Killing experiments showed that fungicidal activity was achieved after 8 h of treatment with G8 at concentrations > or =10 mg/L. In a murine model of systemic cryptococcosis, G8 was effective at prolonging survival compared with the controls. Our data indicate that this new derivative has a potential therapeutic role in infections caused by C. neoformans.

In view of the continuous interest in new DNA cleaving compounds, both for the development of new therapeutic agents and for the possible use as reagents in nucleic acids research, a few pyrazolo[3,4-d][1,2,3]triazole derivatives have been obtained and investigated for their antiproliferative activity and capability to cleave DNA, after light-activation. A possible in situ activation, i.e. in neoplastic tissues, of less cytotoxic derivatives, may lead to potential antitumor compounds endowed with high therapeutic indexes.

Ethyl 2-amino-3-methoxycarbonyl-4-oxo-2-pentenoate (3) reacts with hydroxylamine or hydrazines to give isoxazole and pyrazole ortho-dicarboxylic acid esters 4 and 5, respectively. Partial hydrolysis of diesters 4 and 5 afforded the corresponding dicarboxylic acid monoesters 6 and 7. Amidation of the intermediate acid chlorides 8,9 followed by hydrolysis of 4-methylesters 10, 11 gave the title compounds 1 and 2, respectively.

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.

The synthesis of imidazo[4,5-c]pyrazol-5-ones (6) is reported. 5-Amino-4-ethoxycarbonylaminopyra-zoles 3a-g when heated at 200° for 2 hours afford 6a-g. In a similar manner imidazo[4,5-c]pyrazol-5-one (6a) is readily obtained from 4-amino-5-ethoxycarbonylaminopyrazole (5a).

The syntheses of 4-, 5-, and 6- substituted imidazo[4,5-c]pyrazoles, compounds of potential biological activity, are reported.

An efficient synthesis of pyrazolo[3,4-d]thiazoles (6) was achieved by treatment of N-(4-amino-5-pyrazolyl)thiocarboxamides (4) with sodium nitrite in acidic medium followed by irradiation with uv light

Trente 6-trifluoromethylpyrazolo [3,4-d] pyrimidines ont ete synthetisees et testees pour leur activite antifongique in vitro contre dix champignons phytopathogenes de differentes classes taxonomiques. Six de ces composes ont une action remarquable contre Sclerotinia minor, Corticium solani et Phoma betae. On discute des relations structure-activite sur la base de ces resultats et des etudes anterieures

Douze 6-trifluoromethylpyrazolo [3,4-d] pyrimidine-4(5H)-thiones ont ete synthetisees. On les a testees in vitro pour leur activite fongicide contre une serie de champignons phytopathogenes de differentes classes taxonomiques. Les valeurs EC50 (50% d'inhibition de croissance) et MIC (concentration minimale qui inhibe totalement la croissance) de quatre composes sont comparables ou inferieures a celles de fongicides commerciaux de reference qui controlent Sclerotinia minor, Corticium solani et Pythium ultimum

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.

The reaction of pyrazolo[4,3-c][1,2,5]oxadiazin-3(5H)-ones 1 with carbanions prepared in situ from compounds containing an activated methylene group afforded pyrazolo[3,4-b]pyrazines 4–13 in good yields. The possible reaction mechanism is proposed and discussed.

The reaction of 3H-pyrimido[5,4-c] [1,2,5]oxadiazin-3-one (5) with carbanions prepared in situ from compounds containing an activated methylene group afforded 6,7-disubstituted pteridine-2,4-diones 7a-m in good yields. The reaction mechanism, involving the initial attack by carbanion at oxadiazinone nitrogen atom bonded to oxygen, is proposed and discussed.

Die im Titel genannten Verbindungen (II) werden aus den 5-Aminopyrazol-4-thiocarbonsaureamiden (I) durch Umsetzung mit Ameisensaure/Acetanhydrid erhalten.

The reaction of 3H-pyrimido[5,4-c] [1,2,5]oxadiazin-3-one (5) with carbanions prepared in situ from compounds containing an activated methylene group afforded 6,7-disubstituted pteridine-2,4-diones 7a-m in good yields. The reaction mechanism, involving the initial attack by carbanion at oxadiazinone nitrogen atom bonded to oxygen, is proposed and discussed.

Trichloromethyl chloroformate reacts with N-(1-alkyl/aryl-5-pyrazolyl) thiocarboxamides (2a-j) to give pyrazolo[3,4-d][1,3]thiazin-4-ones (3) while it reacts with N-(3-methyl-5-pyrazolyl)thiobenzamide (2m) to give the pyrazolo[1,5-c] [1,3,5]thiadiazine-4-one (4). Heating under reflux in formic acid of homologues (3g-i) bearing a tert-butyl group linked to pyrazole N-1 atom afforded the dealkylated derivatives (3k-m)