1. Academic Validation
  2. Clicking 3'-azidothymidine into novel potent inhibitors of human immunodeficiency virus

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

  • J Med Chem. 2013 Nov 14;56(21):8765-80. doi: 10.1021/jm401232v.
Venkata Ramana Sirivolu 1 Sanjeev Kumar V Vernekar Tatiana Ilina Nataliya S Myshakina Michael A Parniak Zhengqiang Wang
Affiliations

Affiliation

  • 1 Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
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).

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