Massimo Mura

1,5-Benzodiazepines. Part XII. Synthesis and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepine derivatives as nevirapine analogues

A number of properly substituted 5H-pyrimido[4,5-b][1,5]benzodiazepines (2) and pyrazolo[3,4-b][1,5]benzodiazepines (3 and 4), as well as compounds 5-7, which are derivatives of new tetracyclic systems, were prepared as nevirapine analogues through multistep synthetic routes. The cytotoxic and anti-HIV-1 properties of compounds 2-7 were evaluated in cell-based assays, together with their inhibitory activity against the HIV-1 recombinant reverse transcriptase (rRT) in enzyme assays. The modifications introduced into nevirapine heterocyclic skeleton proved to have a negative effect for the anti-HIV-1 activity. It is worth noting that some of the new derivatives proved to be cytotoxic in the low micromolar range.

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.

Targeting HIV: old and new players.

Despite the unprecedented successes in the therapy of HIV infection, AIDS remains a major world health problem being the first cause of death in Africa and the fourth leading cause of death worldwide. Rapid emergence of drug-resistant HIV variants and severe side effects limit the efficacy of existing therapies. The intrinsic high variability of HIV calls for combining different drugs with distinct mode of action to achieve synergistic antiviral activity. Efforts are being made to develop agents addressing new steps in HIV replication and to optimize both antiviral activity and pharmacokinetic of the current drugs targeting reverse transcriptase and protease. The class of viral entry inhibitors is undergoing evaluation for both systemic and topical administration, and compounds targeting the fusion step may be the first to reach the market. Identification of compounds unambiguously affecting HIV replication by targeting integrase supports the potential of this crucial viral enzyme as a drug target. Targeting HIV gene regulation, which could also lead to cellular toxicity, may also become an important discovery strategy, provided that inhibitors with sufficient specificity are identified. In this review we will summarize the current understanding of the key steps in HIV life cycle in the context of representative inhibitors based on their modes of action. We then present a summary of compounds under clinical development, with the aim of providing a picture of the current potential for targeting HIV.

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.