Clicking 3′-azidothymidine into novel potent inhibitors of human immunodeficiency virus

Venkata Ramana Sirivolu, Sanjeev Kumar V. Vernekar, Tatiana Ilina, Nataliya S. Myshakina, Michael A. Parniak, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)8765-8780
Number of pages16
JournalJournal of medicinal chemistry
Volume56
Issue number21
DOIs
StatePublished - Nov 14 2013

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