Modifications in the alkenyldiarylmethane class of non-nucleoside HIV -1 reverse transcriptase inhibitors providing insight into structure activity relationships
Abstract
In this work, a series of compounds was designed and synthesized as inhibitors of HIV-1 reverse transcriptase, a key enzyme in the life cycle of the virus. The compounds in this work will be useful in understanding the structure-activity relationships in this novel class of HIV-1 non-nucleoside reverse transcriptase inhibitors. Previous studies on the alkenyldiarylmethane series of reverse transcriptase inhibitors have produced nanomolar inhibitors of the cytopathic effect of the HIV-1RF virus in CEM-SS cell culture. Observations derived from this early work in conjunction with molecular modeling techniques led to the development of a hypothetical binding model for the most potent analog. Changes in the architecture of the aromatic region of these inhibitors have allowed structure-activity relationships to be better described. Most notably, this study describes a high degree of structural specificity associated with the aromatic methyl ester functionality. A steric requirement for a functionality with a van der Waals radius of approximately 2 angstroms in the aromatic halogen position is also described. Efforts to substitute the labile aromatic ester moiety with a more robust functionality were unsuccessful. Several modifications in the alkenyl side chain portion of the inhibitors have provided support for the hypothetical binding model. These modifications have also helped to refine a hypothesis concerning activity associated with electronic structure in this region of the molecule.
Degree
Ph.D.
Advisors
Cushman, Purdue University.
Subject Area
Organic chemistry
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