Clicking 3′-Azidothymidine
into Novel Potent Inhibitors of Human Immunodeficiency Virus
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Abstract
3′-Azidothymidine
(AZT) was the first approved antiviral for the treatment of human
immunodeficiency virus (HIV). Reported efforts in clicking the 3′-azido
group of AZT have not yielded 1,2,3-triazoles active against HIV or
any other viruses. We report herein the first AZT-derived 1,2,3-triazoles
with submicromolar potencies against HIV-1. The observed antiviral
activities from the cytopathic effect (CPE) based assay were confirmed
through a single replication cycle assay. Structure–activity-relationship
(SAR) studies revealed two structural features key to antiviral activity:
a bulky aromatic ring and the 1,5-substitution pattern on the triazole.
Biochemical analysis of the corresponding triphosphates showed lower
ATP-mediated nucleotide excision efficiency compared to AZT, which
along with molecular modeling suggests a mechanism of preferred translocation
of triazoles into the P-site of HIV reverse transcriptase (RT). This
mechanism is corroborated with the observed reduction of fold resistance
of the triazole analogue to an AZT-resistant HIV variant (9-fold compared
to 56-fold with AZT)