Application of the Huisgen cycloaddition and 'click' reaction toward various 1,2,3-triazoles as HIV non-nucleoside reverse transcriptase inhibitors.
The development of novel anti-HIV agents remains an important medicinal chemistry challenge given that no cure for the disease is imminent, and the continued use of current NNRTIs inevitably leads to problems associated with resistance. Inspired by the pyrazole-containing NNRTI lersivirine (LSV), we embarked upon a study to establish whether 1,2,3-triazole heterocycles could be used as a new scaffold for the creation of novel NNRTIs. An especially attractive feature of triazoles used for this purpose is the versatility in accessing variously functionalised systems using either the thermally regulated Huisgen cycloaddition, or the related 'click' reaction. Employing three alternative forms of these reactions, we were able to synthesise a range of triazole compounds and evaluate their efficacy in a phenotypic HIV assay. To our astonishment, even compounds closely mimicking LSV were only moderately effective against HIV.
Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
Nicole
N
Pribut
Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
Clinton G L
CG
Veale
AIDS Virus Research Unit, National Institute for Communicable Diseases. Johannesburg, Private Bag X4, Sandringham 2131, Johannesburg, South Africa.
Adriaan E
AE
Basson
Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
Willem A L
WA
van Otterlo
Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa. Electronic address: scpelly@sun.ac.za.
Stephen C
SC
Pelly
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057930:Click Chemistry; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D006678:HIV / Q000187:drug effects*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; D054303:HIV Reverse Transcriptase
HIV reverse transcriptase; Huisgen cycloaddition; Lersivirine; NNRTI; Triazoles