Biomedical subjects

Fabrizia Soragni

Publications and source records attributed to Fabrizia Soragni.

3 recordsLinked to original sources

PubMed2006

Antibacterial agent discovery using thymidylate synthase biolibrary screening.

Thymidylate synthase (TS, ThyA) catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate to 2'-deoxythymidine 5'-monophosphate, an essential precursor for DNA synthesis. A specific inhibition of this enzyme induces bacterial cell death. As a second round lead optimization design, new 1,2-naphthalein derivatives have been synthesized and tested against a TS-based biolibrary, including human thymidylate synthase (hTS). Docking studies have been performed to rationalize the experimentally observed affinity profiles of 1,2-naphthalein compounds toward Lactobacillus casei TS and hTS. The best TS inhibitors have been tested against a number of clinical isolates of Gram-positive-resistant bacterial strains. Compound 3,3-bis(3,5-dibromo-4-hydroxyphenyl)-1H,3H-naphtho[1,2-c]furan-1-one (5) showed significant antibacterial activity, no in vitro toxicity, and dose-response effects against Staphylococcus epidermidis (MIC=0.5-2.5 microg/mL) clinical isolate strains, which are resistant to at least 17 of the best known antibacterial agents, including vancomycin. So far this compound can be regarded as a leading antibacterial agent.

Animals↗

PubMed2004

Analysis of phenolic compounds and radical scavenging activity of Echinacea spp.

The aim of this study was to set up and validate an RP-LC method with DAD-detection to quantify caffeic acid derivatives in various Echinacea spp. Samples were extracted with 80% methanol. The analyses were carried out on a Lichrospher RP-18 column (125 mm x 4 mm i.d., 5 microm), with a mobile phase gradient, which increases the acetonitrile level in a phosphoric acid solution (0.1%). The flow rate was 1.5 ml/min. Detection was set at 330 nm. This method allowed the identification and quantification of caftaric acid, chlorogenic acid, caffeic acid, cynarin, echinacoside and cichoric acid in Echinacea roots and derivatives. The total phenolic content was 10.49 mg/g for E. angustifolia, 17.83 mg/g for E. pallida and 23.23 mg/g for E. purpurea. Among Echinacea commercial herbal medicines, a certain variability in the concentrations of phenolic compounds was observed. The radical scavenging activity of Echinacea methanolic extracts was evaluated in vitro with a spectrophotometric method based on the reduction of an alcoholic 2,2-diphenyl-1-picrylhydrazyl (DPPH*) radical solution at 517 nm in the presence of a hydrogen donating antioxidant. As for pure compounds, echinacoside had the highest capacity to quench DPPH* radicals (EC50 = 6.6 microM), while caftaric acid had the lowest (EC50 = 20.5 microM). The average EC50 values for E. purpurea, E. pallida and E. angustifolia were 134, 167 and 231 microg/ml, respectively. The radical scavenging activity of Echinacea root extracts reflected their phenolic composition. The results indicate that Echinacea roots and derivatives are a good source of natural antioxidants and could be used to prevent free-radical-induced deleterious effects.

Echinacea↗

PubMed2002

Structure-based studies on species-specific inhibition of thymidylate synthase.

Thymidylate synthase (TS) is a well-recognized target for anticancer chemotherapy. Due to its key role in the sole de novo pathway for thymidylate synthesis and, hence, DNA synthesis, it is an essential enzyme in all life forms. As such, it has been recently recognized as a valuable new target against infectious diseases. There is also a pressing need for new antimicrobial agents that are able to target strains that are drug resistant toward currently used drugs. In this context, species specificity is of crucial importance to distinguish between the invading microorganism and the human host, yet thymidylate synthase is among the most highly conserved enzymes. We combine structure-based drug design with rapid synthetic techniques and mutagenesis, in an iterative fashion, to develop novel antifolates that are not derived from the substrate and cofactor, and to understand the molecular basis for the observed species specificity. The role of structural and computational studies in the discovery of nonanalog antifolate inhibitors of bacterial TS, naphthalein and dansyl derivatives, and in the understanding of their biological activity profile, are discussed.

Crystallography, X-Ray↗