Design and synthesis of HIV-1 integrase inhibitors

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.

Name thesis:degree_name

Ph.D. in Pharmaceutical Sciences

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomolecular Sciences

Year dc:date.available

2012

Author dc:creator

• Scarry, Sarah Chajkowski

Contributors dc:contributor

• John M. Rimoldi
• Takashi Tomioka
• Christopher R. McCurdy

• AIDS
• HIV-1 Integrase
• inhibitors
• medicinal chemistry
• oxalamate
• synthesis
• Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://egrove.olemiss.edu/etd/1447

OAI identifier oai:identifier

oai:egrove.olemiss.edu:etd-2446