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Structure-based bioisosterism design, synthesis and biological evaluation of novel 1,2,4-triazin-6-ylthioacetamides as potent HIV-1 NNRTIs.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Dec 01; Vol. 22 (23), pp. 7155-62. Date of Electronic Publication: 2012 Oct 02. - Publication Year :
- 2012
-
Abstract
- The development of new HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) offers the possibility of generating novel chemical entities of increased potency. Previous investigations in our laboratory resulted in the discovery of several novel series of arylazolylthioacetanilides as potent NNRTIs. In this study, based on the structure-based bioisosterism strategy, novel 1,2,4-triazin-6-yl thioacetamide derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. Among them, the most promising compound was 8b15 with double-digit nanomolar activity against wild-type HIV-1 (EC(50)=0.018±0.007 μM) and moderate activity against the double mutant strain RES056 (EC(50)=3.3±0.1 μM), which indicated that 1,2,4-triazin-6-yl thioacetamide can be used as a novel scaffold to develop a new class of potent NNRTIs active against both wild-type and drug-resistant HIV-1 strains. In addition, preliminary structure-activity relationship (SAR) and molecular modeling results are also briefly discussed, which provide some useful information for the further design of novel NNRTIs.<br /> (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)
- Subjects :
- Binding Sites
Cell Line
HIV Reverse Transcriptase metabolism
HIV-1 drug effects
Humans
Molecular Docking Simulation
Protein Structure, Tertiary
Reverse Transcriptase Inhibitors chemistry
Reverse Transcriptase Inhibitors pharmacology
Structure-Activity Relationship
Thioglycolates pharmacology
Triazines pharmacology
Drug Design
HIV Reverse Transcriptase antagonists & inhibitors
HIV-1 enzymology
Reverse Transcriptase Inhibitors chemical synthesis
Thioglycolates chemical synthesis
Thioglycolates chemistry
Triazines chemical synthesis
Triazines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 22
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 23084898
- Full Text :
- https://doi.org/10.1016/j.bmcl.2012.09.062