Fabiana Plescia

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.

Recent advanced in bioactive systems containing pyrazole fused with a five membered heterocycle.

In this review we report the recent advances in bioactive system containing pyrazole fused with a five membered heterocycle, covering the time span of the last decade. All of them are represented around the common structure of the pyrazole ring fused with another five membered heterocycle containing the nitrogen, sulfur and oxygen atoms in all their possible combinations. The classification we have used is based in terms of the therapeutic area providing, when possible, some general conclusions on the targets and mechanisms of action as well as the structure-activity relationships of the molecules.

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 μM, 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.

Pyrazolo[3,4‐d]pyrimidine Derivatives as COX‐2 Selective Inhibitors: Synthesis and Molecular Modelling Studies

The pyrazolo[3,4‐d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti‐inflammatory activity of 5‐benzamido‐pyrazolo[3,4‐d]pyrimidin‐4‐one derivatives and considering the easy synthesis of this class of compounds, a set of new 5‐benzamido‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐ones has been prepared in 42‐80% yields by reacting 5‐aminopyrazole‐4(N‐benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a, b, 10a–d, and 11a, b revealed a superior inhibitory profile against COX‐2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results.

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.

Recent discoveries of anticancer flavonoids

In this review we report the recent advances in anticancer activity of the family of natural occurring flavonoids, covering the time span of the last five years. The bibliographic data will be grouped, on the basis of biological information, in two great categories: reports in which the extract plants bioactivity is reported and the identification of each flavonoid is present or not, and reports in which the anticancer activity is attributable to purified and identified flavonoids from plants. Wherever possible, the targets and mechanisms of action as well as the structure-activity relationships of the molecules will be reported. Also, in the review it was thoroughly investigated the recent discovery on flavonoids containing the 2-phenyl-4H-chromen-4-one system even if some examples of unusual flavonoids, bearing a non-aromatic B-ring or other ring condensed to the base structure are reported.

Synthesis, antiproliferative activity, and mechanism of action of a series of 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides

Several new 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides 12a-s and 17t-v were synthesized by stirring in pyridine the (E)-3-(2-R1-3-R2-4-R3-phenyl)acrylic acid chlorides 11c-k and 11t-v with the appropriate anthranilamide derivatives 10a-c or the 5-iodoanthranilic acid 13. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). COMPARE analysis, effects on tubulin polymerization in cells and with purified tubulin, and effects on cell cycle distribution for 17t, the most active of the series, indicate that these new antiproliferative compounds act as antitubulin agents.

SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF 3-AMINO-N-PHENYL-1H-INDAZOLE-1-CARBOXAMIDES

A series of new 3-amino-N-phenyl-1H-indazole-1-carboxamides 10 have been prepared from commercially available phenyl isocyanate precursors 8 and 3-aminoindazole 9. Some of the synthesized compounds were evaluated for their in vitro antineoplastic activity against 60 human cell lines derived from seven clinically isolated cancer types (lung, colon, melanoma, renal, ovarian, brain, and leukemia) according to the NCI standard protocol. The test results indicated that 3-amino-1H-indazole-1-carboxamides 10 were endowed with an interesting antiproliferative activity. The most active compounds of this series, 10d,e, were able to inhibit cell growth of many neoplastic cell lines at concentrations lower than 1 microM (0.0153 microM in SR leukemia) causing a block in G0-G1 phase of cell cycle. Analysis of pRb expression showed that these two compounds increased the ratio between underphosphorylated pRb and total pRb. The X-ray structure of 10w, confirmed the 3-amino-N-phenyl-1H-indazole-1-carboxamide structure of compounds 10.

Synthesis and antiproliferative activity of 3-(2-chloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one

Based on the encouraging results found for 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 7 previously tested by us, as well as the consideration that heterocycle fused tetrazepinones bearing the 2-chloroethyl substituent show a better cytotoxic profile than temozolomide and mitozolomide against human cancer cell lines which express the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), in this paper we report the multistep synthesis and the biological study of 3-(2-chloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 10. Like compound 7, it was active on P-glycoprotein expressing cells (MDR) HL60 and on K562 cell line that are resistant to apoptosis induced by different stimuli, showing GI50 values of 14 and 18 μM respectively. As an antiproliferative agent against the above cells compound 10 was about 2.2 times more active than compound 7. Compound 10 was also tested against WiDR cells which are overexpressing the DNA repair protein MGMT, showing a GI50 value of 2.3 μM. Finally, concerning the effect on cell cycle we observed an evident difference between compounds 7 and 10. In fact, compound 7 induces a block of cell cycle in G0-G1, therefore acting as phase-specific drug, in contrast, compound 10 is a not phase-specific agent. Both the compounds are able to increase the apoptotic sub G0-G1 peak of cell cycle.

Synthesis and anti-staphylococcal activity of new 4-diazopyrazole derivatives

Several new 4-diazopyrazole derivatives 6a-g and 9a-c were obtained by the reaction of 1-(R-substituted-phenyl)-3-(1,3-dimethyl-1H-pyrazol-5-yl)ureas 5a-g and N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(R-substituted-phenyl)acetamides 8a-c respectively with a sevenfold excess of nitrous acid in acetic acid solution. The compounds were assayed for their activity against the Staphylococcus aureus reference strains ATCC 25923, ATCC 29213 and ATCC 6538, as well as six veterinary strains. The best anti-staphylococcal profile was showed by [(R-substituted-phenyl)acetyl](4-diazonio-1,3-dimethyl-1H-pyrazol-5-yl)azanides 9a,c. Compound 9c was also able at 3.1 μg mL(-1) to inhibit of 45.7% the biofilm formation of the strains S. aureus ATCC 29213.