Electronic Theses and Dissertations

Date of Award

1-1-2012

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Biomolecular Sciences

First Advisor

John M Rimoldi

Second Advisor

Takashi Tomioka

Third Advisor

Christopher R. McCurdy

Relational Format

dissertation/thesis

Abstract

In recent years, HIV-1 integrase (IN) has emerged as an attractive target for the treatment of human immunodeficiency virus type 1 (HIV-1), the causative pathogen of acquired immuno-deficiency syndrome (AIDS). Several classes of IN inhibitors are known but many of these compounds are toxic, do not show antiviral activity or display decreased potency. Therefore, new classes of potent IN inhibitors are desperately needed. The b-diketo (b-DK) class of compounds has emerged as one of the most successful classes of IN inhibitors. Although several b-DK inhibitors with potent antiviral activity are known, compounds containing b-DK motifs have limitations in drug development. The overall objective of this dissertation was to design and synthesize a novel series of IN inhibitors that retain the favorable characteristics of the b-DK scaffolds but are devoid of the "undruggable" properties. The design of the target molecules was established from crystal structure-based correlation and structure-activity relationship studies, which led to scaffolds containing three specific functional groups. Each molecule was designed to contain the core functional motif (a,b-diketoamide), optimal aryl groups (3-benzylphenyl or substituted 3-benzylphenyl) and a terminal group (proton donor or acceptor or amphoteric functional groups) in a planar or near planar configuration. Several oxalamate containing compounds were successfully designed and synthesized; and many of these synthetic analogs were sent to be screened for inhibitory activity against HIV-1 IN. The synthetic analogs described herein may elicit alluring antiviral activity, serve as potential lead molecules for future optimizations and ultimately elucidate mechanistic insight into HIV-1 IN inhibition.

Concentration/Emphasis

Emphasis: Medicinal Chemistry

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