Alessandra Cadeddu

2'-C-Methyl branched pyrimidine ribonucleoside analogues : potent inhibitors of RNA virus replication

RNA viruses are the agents of numerous widespread and often severe diseases. Their unique RNA-dependent RNA polymerase (RDRP) is essential for replication and, thus, constitutes a valid target for the development of selective chemotherapeutic agents. In this regard, we have investigated sugar-modified ribonucleoside analogues as potential inhibitors of the RDRP. Title compounds retain ‘natural’ pyrimidine bases, but possess a β-methyl substituent at the 2′-position of the D- or L-ribose moiety. Evaluation against a broad range of RNA viruses, either single-stranded positive (ssRNA), single-stranded negative (ssRNA−) or double-stranded (dsRNA), revealed potent activities for D-2′-C-methyl-cytidine and -uridine against ssRNA+, and dsRNA viruses. None of the L-enantiomers were active. Moreover, the 5′-triphosphates of the active D-enantiomers were found to inhibit the bovine virus diarrhoea virus polymerase. Thus, the 2′-methyl branching of natural pyrimidine ribonucleosides transforms physiological molecules into potent, broad-spectrum antiviral agents that merit further development.

Isolation of Juniperus phoenicea Volatiles by Supercritical Carbon Dioxide Extraction and Bioactivity Assays

Abstract By means of a supercritical fluid extractor, extract of Juniperus phoenicea L. was obtained in a single extraction stage. The yield was 0.2% by mass. The operative conditions were: extractor, pressure, P = 90 bar and temperature, T = 50°C; first separator, P = 90 bar and T = −10°C; second separator, P = 15 bar and T = 10°C. The hydrodistilled oil gave a yield of 0.3% by mass. In both extracts, the three compounds present in the biggest quantity were: α-pinene (18.4 versus 13.9% in the SFE and HD oil, respectively), germacrene D (14.3 versus 8.1%) and β-caryophyllene (8.7 versus 5.4%). The extracts obtained at different pressures were tested for antiviral, antiproliferative and antimicrobial activities. The results showed that the extracts obtained at 200 and 300 bar were cytotoxic against different cell lines and were active against a single-stranded RNA+ virus. The extracts containing the most cytotoxic active principles showed also antiproliferative activity against a panel of human cell lines derived from liquid and solid tumors. When tested for antimicrobial activity none of the samples resulted active.

Hindered nucleoside analogs as antiflaviviridae agents

Flaviviridae are an important family of viruses, responsible for widely spread diseases such as dengue and West Nile fever and hepatitis C. Despite the severity of the related diseases, no effective antiviral treatments for infection are available. Following our discovery of adenosine-hindered analogs as potent antiflaviviridae agents, we have continued our investigation on guanosine and inosine derivatives, which were evaluated for activity against BVDV, YFV, DENV, and WNV viruses in cell-based assays. The present study allowed us to identify some newer features that led to improve the antiviral potency (down to the µM range) and to selectively inhibit BVDV and YFV viruses. The molecular modeling results were consistent with the hypothesis that test analogs act as RNA-dependent RNA polymerase (RdRp) inhibitors by interacting with a surface allosteric binding pocket.

Synthesis and antiviral evaluation of 7-fluoro-7-deaza-2-aminopurine nucleoside derivatives.

Three 7-fluoro-7-deaza-2-aminopurine nucleoside derivatives were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).

Synthesis and antiviral evaluation of 4-fluoropyrazole-3-carboxamide nucleoside derivatives

A series of novel 4-fluoro-1H-pyrazole-3-carboxamide nucleoside analogues were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).