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

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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...

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Main Author: Mohamed, Ebrahim
Other Authors: Hunter, Roger
Format: Thesis
Language:English
Published: Department of Chemistry 2024
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Chemistry
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_version_ 1867613266612584448
access_status_str Open Access
author Mohamed, Ebrahim
author2 Hunter, Roger
author_browse Hunter, Roger
Mohamed, Ebrahim
author_facet Hunter, Roger
Mohamed, Ebrahim
author_sort Mohamed, Ebrahim
collection Thesis
description 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. Chapter Two describes the first series involving the synthesis of bifunctional HIV-drugs using d4U as the NRTI and UC-781 as the NNRTI. This resulted in two unthiated UC-781/d4U entities being synthesized in a convergent manner in 16 steps for the pentane-propyne target and 20 steps for the target bearing PEG-propyne units using Sonogashira coupling methodology as a key step. Chapter Three describes the second series incorporating a new NNRTI in the form of 2- and 4- pyrimidinylarylamine motifs. Key features in this chapter include the synthesis of tri-substituted anilines, the library generation of 2- and 4-pyrimidinylarylamine derivatives as model NNRTIs, as well as Sonogashira coupling reactions to obtain three bifunctional targets. The final part of this thesis describes the synthesis of a remarkable d4U/TMC120 bifunctional system, synthesized on the basis of molecular modeling. Biological results indicate that the d4U4-PEG-TMC120 bifunctional has the lowest EC50 anti-HIV activity of any NRTI-spacer-NNRTI bifunctional inhibitor synthesized to date. The NRTI was also triphosphorylated and the product evaluated in an in vitro RT inhibition assay, which culminated in a 'proof of principle' of synergy existing between the substrate site and the allosteric binding pocket. Also presented, is work carried out to change the rigid d4U to a more flexible acyclic nucleotide phosphonate in a pronucleotide approach. A range of conclusions on the work are presented at the end.
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institution University of Cape Town (South Africa)
language eng
last_indexed 2026-06-10T12:33:25.185Z
license_str Not specified — see source repository
provenance_str_mv Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository
publishDate 2024
publishDateRange 2024
publishDateSort 2024
publisher Department of Chemistry
publisherStr Department of Chemistry
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source_str UCTD — University of Cape Town Open Access Repository
spelling oai:open.uct.ac.za:11427/39359 Probing the HIV Reverse-Transcriptase enzyme with novel bifunctional HIV-1 RT inhibitors of the general formula (NRTI)-spacer-(NNRTI) Mohamed, Ebrahim Hunter, Roger Chemistry 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. Chapter Two describes the first series involving the synthesis of bifunctional HIV-drugs using d4U as the NRTI and UC-781 as the NNRTI. This resulted in two unthiated UC-781/d4U entities being synthesized in a convergent manner in 16 steps for the pentane-propyne target and 20 steps for the target bearing PEG-propyne units using Sonogashira coupling methodology as a key step. Chapter Three describes the second series incorporating a new NNRTI in the form of 2- and 4- pyrimidinylarylamine motifs. Key features in this chapter include the synthesis of tri-substituted anilines, the library generation of 2- and 4-pyrimidinylarylamine derivatives as model NNRTIs, as well as Sonogashira coupling reactions to obtain three bifunctional targets. The final part of this thesis describes the synthesis of a remarkable d4U/TMC120 bifunctional system, synthesized on the basis of molecular modeling. Biological results indicate that the d4U4-PEG-TMC120 bifunctional has the lowest EC50 anti-HIV activity of any NRTI-spacer-NNRTI bifunctional inhibitor synthesized to date. The NRTI was also triphosphorylated and the product evaluated in an in vitro RT inhibition assay, which culminated in a 'proof of principle' of synergy existing between the substrate site and the allosteric binding pocket. Also presented, is work carried out to change the rigid d4U to a more flexible acyclic nucleotide phosphonate in a pronucleotide approach. A range of conclusions on the work are presented at the end. 2024-04-11T13:29:49Z 2024-04-11T13:29:49Z 2009 2024-04-11T12:52:51Z Thesis / Dissertation Doctoral PhD http://hdl.handle.net/11427/39359 eng application/pdf Department of Chemistry Faculty of Science
spellingShingle Chemistry
Mohamed, Ebrahim
Probing the HIV Reverse-Transcriptase enzyme with novel bifunctional HIV-1 RT inhibitors of the general formula (NRTI)-spacer-(NNRTI)
thesis_degree_str Doctoral
title Probing the HIV Reverse-Transcriptase enzyme with novel bifunctional HIV-1 RT inhibitors of the general formula (NRTI)-spacer-(NNRTI)
title_full Probing the HIV Reverse-Transcriptase enzyme with novel bifunctional HIV-1 RT inhibitors of the general formula (NRTI)-spacer-(NNRTI)
title_fullStr Probing the HIV Reverse-Transcriptase enzyme with novel bifunctional HIV-1 RT inhibitors of the general formula (NRTI)-spacer-(NNRTI)
title_full_unstemmed Probing the HIV Reverse-Transcriptase enzyme with novel bifunctional HIV-1 RT inhibitors of the general formula (NRTI)-spacer-(NNRTI)
title_short Probing the HIV Reverse-Transcriptase enzyme with novel bifunctional HIV-1 RT inhibitors of the general formula (NRTI)-spacer-(NNRTI)
title_sort probing the hiv reverse transcriptase enzyme with novel bifunctional hiv 1 rt inhibitors of the general formula nrti spacer nnrti
topic Chemistry
url http://hdl.handle.net/11427/39359
work_keys_str_mv AT mohamedebrahim probingthehivreversetranscriptaseenzymewithnovelbifunctionalhiv1rtinhibitorsofthegeneralformulanrtispacernnrti

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