Synthesis of N-Hydroxypyrazinones as Potential HIV Inhibitors

摘要

Hydroxamic acids, with the two bioactive representatives aspergillic acid (naturally occurring) and vorinostat (synthetic), are well known for their strong binding ability with many metal ions. This explains their potential to inhibit specific metal-containing enzymes involved in e.g. human immunodeficiency virus and cancer progression. Our group has previously been working on the design and synthesis of highly functionalized pyrazinones. Therefore, it was of interest to us to combine these two classes of compounds into new compounds resembling integrase inhibitor diketoacid-based structures and histone deacetylase inhibitors.Functionalization of C-3 of N-hydroxypyrazinones has been thoroughly investigated in this thesis resulting in the successful synthesis of a library containing three series of novel compounds, including 3-alkyl-/carboxamide-/ureidoalkyl-1-hydroxypyrazinones.With the implemention of flow chemistry technology and catalytic transfer hydrogenation, we have succeeded in delivering a reproducible methodology for the selective debenzylation of O-benzyl protected N-hydroxypyrazinones, with a potential for scaling up to gram scale on suitable flow apparatus.Numerous N-hydroxypyrazinones have been synthesized with HIV inhibitory activity in mind. However, in vitro evaluation of anti-HIV-1 and HIV-2 replication on human T-lymphocyte cells using an MTT assay showed that none of the synthesized compounds exhibits the inhibitory activity. Some compounds do however show inhibition in an HIV-1 reverse transcriptase polymerase assay.