Demetrio Raffa

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.

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, anti-inflammatory activity, and in vitro antitumor effect of a novel class of cyclooxygenase inhibitors: 4-(aryloyl)phenyl methyl sulfones.

Following our previous research on anti-inflammatory drugs (NSAIDs), we report on the design and synthesis of 4-(aryloyl)phenyl methyl sulfones. These substances were characterized for their capacity to inhibit cyclooxygenase (COX-1 and COX-2) isoenzymes. Molecular modeling studies showed that the methylsulfone group of these compounds was inserted deep in the pocket of the human COX-2 binding site, in an orientation that precludes hydrogen bonding with Arg120, Ser353, and Tyr355 through their oxygen atoms. The N-arylindole 33 was the most potent inhibitor of COX-2 and also the most selective (COX-1/COX-2 IC(50) ratio was 262). The indole derivative 33 was further tested in vivo for its anti-inflammatory activity in rats. This compound showed greater inhibitory activity than ibuprofen. Other compounds (20, 26, 9, and 30) showed strong activity against carrageenan-induced inflammation. The latter compounds showed a weak capacity to inhibit the proliferation of human cell lines K562, NCI-H460, and HT-29 in vitro.

Antimicrobial and antineoplastic activities of new 4-diazopyrazole derivatives

Abstract Several new 4-diazopyrazole derivatives were prepared by the reaction of 3-methyl-5(substituted-benzamido)pyrazoles with an excess of nitrous acid in acetic acid solution. The compounds were tested for antiretroviral activity in HIV-1 infected MT-4 cells and antiproliferative effects against a panel of human leukemia, lymphoma and solid tumor cell lines. They were also tested for activity against representative gram-negative ( Shigella, Salmonella ) and gram-positive ( S. aureus, D group Streptococcus ) bacteria as well as fungi ( C. albicans, C. paratropicalis, C. neoformans and A. fumigatus ). Compounds were devoid of anti HIV-1 and antimicotic activities, whereas they were active against tumor cell lines, with inhibitory activity (IC 50 ) in the range 2.4–20 μM and bacteria. The highest microbial susceptibility was shown by gram-positive bacteria, with minimum inhibitory concentrations in the range 0.8–12.5 μM.

Synthesis and pharmacological study of ethyl 1-methyl-5-[2-substituted-4-oxo-3(4H)-quinazolinyl]-1H-pyrazole-4-acetates

Abstract A number of new ethyl 1-methyl-5-[4-oxo-3(4 H )-quinazolinyl]-1 H -pyrazole-4-acetates substituted at the 2 position of the quinazolinone ring were prepared. The compounds were tested for analgesic and antiinflammatory activities, as well as for their acute toxicity and ulcerogenic effect. The 2-methyl, 2-ethyl and 2-phenyl derivatives proved to be more active than acetylsalicylic acid and phenylbutazone in the phenylbenzoquinone writhing test. The 2-methyl derivative was also as active as acetylsalicylic acid in the carrageenin paw oedema test. All the compounds showed very reduced ulcerogenic effects and systemic toxicity.

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.

Sortase A Inhibitors: Recent Advances and Future Perspectives

Here, we describe the most promising small synthetic organic compounds that act as potent Sortase A inhibitors and cater the potential to be developed as antivirulence drugs. Sortase A is a polypeptide of 206 amino acids, which catalyzes two sequential reactions: (i) thioesterification and (ii) transpeptidation. Sortase A is involved in the process of bacterial adhesion by anchoring LPXTG-containing proteins to lipid II. Sortase A inhibitors do not affect bacterial growth, but they restrain the virulence of pathogenic bacterial strains, thereby preventing infections caused by Staphylococcus aureus or other Gram-positive bacteria. The efficacy of the most promising inhibitors needs to be comprehensively evaluated in in vivo models of infection, in order to select compounds eligible for the treatment of bacterial infections in humans.

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.