Abstract
Starting from the potent antiviral agent BCH-189 and taking a rational structure-based design approach, a series of nucleotide and nucleoside analogues were designed and a novel synthetic protocol amenable towards Structure-Activity Relationship study purposes was established. Using this synthetic process, a series of 3'-heteroatom substituted dideoxynucleosides as well as their corresponding nucleotides were generated. Additionally and with minor modifications, the abovementioned process was amended to allow for the synthesis of 2'-heteroatom substituted dideoxynucleosides and nucleotides, both series of which were also arrived at chemically. Representative members of the 3'-heteroatom containing nucleosides mentioned above were further elaborated to the corresponding mono-phosphonate to investigate a recent hypothesis in antiviral prodrug design. In a similar structure-based approach starting with well known antiviral agents HPMPA and PMEA, cyclic and phosphonate-containing nucleosides were conceptualized, a synthetic route towards their generation delineated, and members thereof arrived at synthetically.Most of the derivatives arrived at in the abovementioned synthetic work were subjected to antiviral potential evaluation against viruses responsible for a wide range of viral indications of significance. Although significant antiviral activity from these cell based assays has yet to emerge, those against HBV and HIV, the two specific targets of this sub-project, are eagerly anticipated. Otherwise each of these derivatives exhibited a unique antiangiogenic profile. In the presence of all, compound 109 showed the better in vitro potency against VEGF migration or tube formation.Apart from the aforementioned work towards the generation of novel and potentially therapeutically useful antiviral agents, a project relying on a rational structure-based design of novel antipsychotic agents was achieved. Starting from diarylmethylene-piperidine derivative 133, a known molecule possessing antipsychotic properties, a series of 1,3-dioxolane and 1,3-oxathiolane containing derivatives were designed and synthesized via a highly convergent synthetic protocol. In vitro assays of these compounds yielded several promising lead structures amenable towards the development of novel antipsychotic therapeutics.