Synthesis of phosphorus/sulfur-based antivirals

The Human Immunodeficiency Virus is a major global health problem. Although a number of effective combination therapies are available, drug resistance remains an ongoing concern due to the rapid mutation rate of the virus. Novel antivirals are continually required to combat evolving resistance. By making structural modifications to existing antiviral agents, the rate of antiviral incorporation into the viral DNA chain may be accelerated leading to more rapid termination of viral replication. Chapter 1 discusses the strategy of bioisosteric replacement and the rationale for choosing the phosphonodithioate functional group as a suitable bioisostere. An in-depth review of the conversion of alkyl halides to alcohols is also outlined in this chapter. The preparation of the antiviral agent adefovir is detailed in Chapter 2. The derivatisation of adefovir via the corresponding phosphonic dichloride intermediate and under Garegg-Samuelsson reaction conditions is further discussed. The preparation of novel butyl and dibutyl phosphonate analogues of adefovir using both approaches is described. Attempted coupling of the corresponding sulfur-based analogues is also outlined in this chapter. A synthetic route to two novel phosphonodithioate-containing alcohols is detailed in Chapter 3. Installation of the key carbon-nitrogen bond under Mitsunobu conditions is explored with this strategy ultimately proving unsuccessful. Chapter 4 outlines the preparation of aryl-linked phosphonates and phosphonic acids via copper-catalysed Chan-Lam coupling of adenine-derived nucleobases with boronic acids and esters. Ten novel aryl-linked phosphonates/phosphonic acids were successfully synthesised and have been evaluated for activity against HIV and hepatitis B. The application of this synthetic strategy to phosphonodithioate-containing compounds is also discussed. Computational analysis of our novel aryl-linked analogues is described in Chapter 5. The physicochemical properties of each compound are evaluated against Lipinski’s Rules and Veber’s Rules while the compounds have also been screened for PAINS alerts and organ-specific toxicities. 3D analysis of these compounds is also presented. Chapter 6 details our main conclusions and future work on this project while full experimental procedures, including spectroscopic and analytical data, is outlined in Chapter 7.

Grantor dc:publisher

University College Cork

Year dc:date.issued

2025

Author dc:creator

• Collins, Emily Agnes

Advisor dc:contributor.advisor

• O'Sullivan, Tim

• HIV
• AIDS
• DNA
• RNA
• Retrovirus
• Antiviral
• NRTI
• Acyclic
• Adefovir
• Oxygen
• Sulfur
• Phosphorus
• Garegg-Samuelsson
• Mitsunobu
• Chan-Lam
• Biological
• Evaluation
• Computational
• Nucleoside
• Phosphonate
• SATE
• POM
• Microwave
• Finkelstein
• Arbuzov
• Borylation
• Hepatitis
• Phosphonodithioate
• Phosphonothioate

Statement dc:rights

• © 2025, Emily Agnes Collins.

Licence dc:rights.uri

• https://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10468/18922

OAI identifier oai:identifier

oai:cora.ucc.ie:10468/18922