Publications

The anti-HIV agent cosalane inhibits both the binding of gp120 to CD4 as well as an undefined postattachment event prior to reverse transcription. Several cosalane analogues having an extended polyanionic "pharmacophore" were designed based on a hypothetical model of the binding of cosalane to CD4. The analogues were synthesized, and a number of them displayed anti-HIV activity. One of the new analogues was found to possess enhanced potency as an anti-HIV agent relative to cosalane itself. Although the new analogues inhibited both HIV-1 and HIV-2, they were more potent as inhibitors of HIV-1 than HIV-2. Mechanism of action studies indicated that the most potent of the new analogues inhibited fusion of the viral envelope with the cell membrane at lower concentrations than it inhibited attachment, suggesting inhibition of fusion as the primary mechanism of action.

Abstract The α‐hydroxybenzylphosphonates 1a–1j of the antiviral drug 3′‐azido‐2′,3′‐dideoxythymidine 5 (AZT) as potential lipophilic prodrugs were readily accessible in 49% to 87% yield via a four‐step synthetic pathway introducing the modifications in the aromatic ring system in the last step by making use of intermediate 6. All compounds 1a–1j exhibited higher partition coefficients in 1‐octanol/water than AZT (5) . In hydrolysis studies at pH 7.5 we observed that precursors to bioactive compounds were delivered by simple hydrolysis of the lipophilic precursors 1a–1j via two different mechanisms: the phosphonate‐phosphate rearrangement leading to the benzylphosphotriesters 2 and/or the direct cleavage into the di‐AZT phosphonate 6. Both compounds 2 and 6 were further degraded yielding the potentially antiviral active compounds 4 and 8 , respectively. The hydrolysis pathway could be controlled by the substitution pattern in the benzylic moiety. Identical hydrolytic behavior of 1 was detected in „biological”︁ hydrolysis kinetics by using a RPMI culture medium containing 10% heat‐inactivated fetal calf serum (FCS). The title compounds 1a–1j exhibited considerable HIV‐1 and HIV‐2 activity in wild‐type CEM/O cells.

Novel chain-extended nucleoside phosphoramidates of the anti-human immunodeficiency virus (HIV) drug d4T (stavudine) have been prepared as possible membrane-permeable prodrugs of the bio-active free 5'-monophosphates. Phosphorochloridate chemistry gave the target compounds in moderate to high yields, and all materials were fully characterized by spectroscopic and analytical methods. The compounds are related to the previously reported phenyl methoxyalaninyl derivative of d4T, which was shown to be a potent and selective inhibitor of HIV. In this study the amino acid nitrogen and ester moieties were separated by methylene spacers of between two and six carbon atoms. In vitro evaluation of these compounds indicated an almost complete lack of anti-HIV activity, the compounds being several orders of magnitude less potent than the corresponding alpha-amino acid derivatives. The reasons for the virtual lack of anti-HIV activity appear to involve poor enzyme-mediated hydrolysis.

Varicella-zoster virus (VZV) is responsible for primary infections as well as reactivations after latency in the dorsal root ganglia. The treatment of such infections is mandatory for immunocompromised patients and highly recommended for elderly patients with herpes zoster infections (also called zona or shingles). The treatment of choice is presently based on four molecules, acyclovir (ACV), valaciclovir, famciclovir, and (in Europe) brivudine (BVDU). We present here our data on the antiviral activity of a new class of potent and selective anti-VZV compounds, bicylic pyrimidine nucleoside analogues (BCNAs), against a broad variety of clinical isolates and different drug-resistant virus strains. The results show that the BCNAs are far more potent inhibitors than ACV and BVDU against clinical VZV isolates as well as the VZV reference strains Oka and YS. The BCNAs were not active against ACV- and BVDU-resistant VZV strains bearing mutations in the viral thymidine kinase gene but kept their inhibitory potential against virus strains with mutations in the VZV DNA polymerase gene. Mutant virus strains selected in the presence of the BCNAs were solely cross-resistant to drugs, such as ACV and BVDU, that depend for their antiviral action on metabolic activation by the viral thymidine kinase.