NEW PHENYL NUCLEOSIDES AS ANTI-HIV AGENTS

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DESCRIPTION (provided by applicant): Due to the fatal nature of acquired immunodeficiency syndrome (AIDS), an intensive effort has been underway to develop new therapies or to improve existing therapies for the treatment of AIDS. Among the various structural classes of the antiviral agents investigated for the tretment of human imunodeficiency virus (HIV-1), a virus resposnsible for AIDS disease, nucleoside analogues are among the most effective. Although these nucleoside analogues, dideoxynucleosides and their carbocyclic analogs, offer great promise for the inhibition of viral replication, several shortcomings (resistance, side effects etc.) limit their use as effective therapeutic agents. Therefore, there is a critical need for the development of new potent and less toxic antiviral drugs/leads for the treatment of AIDS. Our approach to uncover new structural "lead" is to explore the nucleoside analogue structures which include a carbocycle (or various modifications thereof) wherein the conformational restrains imposed by the presence of a double bond (pi electrons) has resulted in potent antiviral activity. Therefore, in the search for a new lead as potential anti-HIV agents we hypothesize that the replacement of a dideoxynucleoside sugar ring with a rationally substituted, pi double bond rich, phenyl carbocyclic ring might mimic the required distance/electronic distribution, as in nucleosides, between the N9-puine/Nl-pyrimidine and the C5' for the binding to both target and nontarget macromolecules and this may result, at least in part, in the therapeutic as well as toxic actions of the drug. To test this hypothesis, we propose to conduct the following studies: a) design and synthesize a series of new phenylpurine and phenylpyrimidine compounds, b) conduct adenosine deaminase experiments with adenine compounds to establish the analogy with the nucleosides, and c) evaluate in-vitro activity against HIV-1. Nucleoside analogues are also effective against herpesvirus infections such as herpes simples virus (HSV), varicella zoster virus (VZV), human cytomegalovirus (HCMV), and Epstein-Barr virus (EBV), therefore we will also test these phenyl compounds against these viruses. The information gained in this project will be valuable not only in determining the mechanism of action and structure-activity relationship of these new phenyl nucleosides, but may also result in the development of a selective and potent anti-HIV agent.