New anti-HIV agents. Part I. The alkenyldiarylmethanes as non-nucleoside reverse transcriptase inhibitors. Part II. Design and synthesis of two series of cosalane analogs
Abstract
The use of triple drug combinations has resulted in significant progress in the treatment of HIV infections. However, problems related to development of resistance, drug incompatibilities, and patient intolerance emphasize the need for new AIDS therapies. In the present study, two essential steps of the HIV life cycle have been targeted for the development of new therapeutic agents. The alkenyldiarylmethanes (ADAMs), a recently reported class of non-nucleoside inhibitors (NNRTIs), was further developed to improve the antiviral potency with the design and synthesis of a new set of compounds. Two analogs, termed ADAM II-Cl and ADAM II-Br, displayed excellent anti-HIV-1 potency and therapeutic index. Results obtained from different mechanisms of action assays and resistance mutation studies confirmed the mode of action of these compounds. The use of these ADAMS as new leads for the design of more potent analogs and the potential clinical utility of this class of NNRTIs against AZT resistant strains of HIV-1 are suggested based on the results derived from this work. Interference with the entry of HIV to the cell was targeted in the second part of this study with the design and synthesis of two series of cosalane analogs. Cosalane is a novel anti-HIV agent that acts primarily by inhibition of viral attachment and fusion. In the first set of compounds, the linker chain of cosalane was altered by incorporating amido or amino groups. Only certain compounds possessing an amido moiety displayed anti-HIV activity. The incorporation of an amino group gave inactive derivatives. In the second set of congeners, two units of the cosalane pharmacophore were attached to the steroid ring with appropriate linker chains. The position of the pharmacophore groups and the length and composition of the linker were varied. The most potent compound of this series, which showed an approximate four-fold increase in anti-HIV-1 potency over the lead, had the pharmacophore units attached at C-3 and C-17 of the steroid with a linker chain length equal to that present in cosalane. It was thus demonstrated that having additional pharmacophore units is an attractive approach for increasing the anti-HIV potency in the cosalane series.
Degree
Ph.D.
Advisors
Cushman, Purdue University.
Subject Area
Organic chemistry
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