Probing the HIV reverse-transcriptase enzyme with novel bifunctional HIV-1 RT inhibitors of the general formula (NRTI)-spacer-(NNRTI)

The high levels of resistance elicited by both nucleoside (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors have prompted the design of double-drugs combining these two entities with the aim of addressing the emergence of resistance as well as searching for synergism between the two drug target sites on HIV reverse transcriptase (RT). The strategy involves combining two different inhibitors into a single chemical entity via a linker, with the aim of developing a mixed-site inhibitor combining the inhibitory actions of each drug. This thesis describes the rational drug-design and synthesis of nine bifunctional drugs combining a nucleos(t)ide and a non-nucleoside reverse transcriptase inhibitor linked via different non-cleavable spacers. The C-5 position of the nucleos(t)ide portion of the bifunctional was used for attachment of the spacer throughout. However, the site of attachment on the nonnucleoside drug varies according to the inhibitor type.

Grantor dc:publisher.institution

Department of Chemistry

Year dc:date.issued

2009

Author dc:creator

• Mohamed, Ebrahim

Advisor dc:contributor.advisor

• Hunter, Roger

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/11427/12152

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/12152