Clicking 3′-Azidothymidine into Novel Potent Inhibitors of Human Immunodeficiency Virus
Venkata Ramana Sirivolu,Sanjeev Kumar V. Vernekar,Tatiana V Ilina,Nataliya S. Myshakina,Michael A. Parniak,Zhengqiang Wang +5 more
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TLDR
The first AZT-derived 1,2,3-triazoles with submicromolar potencies against HIV-1 are reported, confirming a mechanism of preferred translocation of triazoles into the P-site of HIV reverse transcriptase (RT).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 t...read more
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Medicinal attributes of 1,2,3-triazoles: Current developments
TL;DR: The present work aims to summarize the current approaches adopted for the synthesis of the 1,2,3-triazole and medicinal significance of these architectures as a lead structure for the discovery of drug molecules such as COX-1/COX-2 inhibitors, HIV protease inhibitors, CB1 cannabinoid receptor antagonist and much more which are in the pipeline of clinical trials.
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Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications.
TL;DR: The ruthenium-catalyzed azide alkyne cycloaddition affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-Catalyzed reaction providing the 1,4-isomer.
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Design, synthesis, biochemical, and antiviral evaluations of C6 benzyl and C6 biarylmethyl substituted 2-hydroxylisoquinoline-1,3-diones: dual inhibition against HIV reverse transcriptase-associated RNase H and polymerase with antiviral activities.
Sanjeev Kumar V. Vernekar,Zheng Liu,Eva Nagy,Lena Miller,Karen A. Kirby,Daniel J. Wilson,Jayakanth Kankanala,Stefan G. Sarafianos,Michael A. Parniak,Zhengqiang Wang +9 more
TL;DR: A novel variant of 2-hydroxyisoquinoline-1,3-dione (HID) scaffold featuring a crucial C-6 benzyl or biarylmethyl moiety, previously unknown chemotypes, consistently inhibited HIV RT-associated RNase H and polymerase with IC50s in low to submicromolar range.
Journal ArticleDOI
5'-Silylated 3'-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus.
Sanjeev Kumar V. Vernekar,Li Qiu,Jing Zhang,Jayakanth Kankanala,Hongmin Li,Hongmin Li,Robert J. Geraghty,Zhengqiang Wang +7 more
TL;DR: A 5'-silylated nucleoside scaffold derived from 3'-azidothymidine (AZT) consistently and selectively inhibiting WNV and DENV at low micromolar concentrations is reported, with particularly interesting is the 5' silyl group which turns on the antiviral activity against WNV while abrogating the previously reported antiviral potency against human immunodeficiency virus (HIV-1).
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Efficient synthesis of 1,2,3-triazoles by copper-mediated C-N and N-N bond formation starting from N-tosylhydrazones and amines.
TL;DR: Preliminary mechanistic studies indicated that the reaction probably proceeded through a 1-tosyl-2-vinyldiazene intermediate and subsequent aza-Michael addition and N-N bond formation process.
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