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Design, synthesis and biological evaluation of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives as HIV-1 NNRTIs.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2013 Nov 15; Vol. 21 (22), pp. 7091-100. Date of Electronic Publication: 2013 Sep 14. - Publication Year :
- 2013
-
Abstract
- A series of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives (PTTDs) was designed and synthesized by a facile route. The biological assay results showed that five most potent compounds displayed inhibitory activity against HIV-1 at low micromolar concentrations (EC50=5.1-8.9 μM). Structure-activity relationship analysis indicated that N2-(3-halogenated-benzyl) analogues were more potent than N2-(unsubstituted-benzyl) analogues. The N4-substitutions contributed to the antiviral activity in the following order: 2-/3-cyano substituted benzyl > 2-/3-halogenated benzyl > non-substituted benzyl > 4-halogenated benzyl. Docking studies of the representative compound revealed the binding conformation of these compounds and provided critical insights for the further development of PTTD analogues.<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Subjects :
- Binding Sites
Cell Line
HIV Reverse Transcriptase metabolism
HIV-1 enzymology
Humans
Inhibitory Concentration 50
Molecular Docking Simulation
Protein Structure, Tertiary
Reverse Transcriptase Inhibitors chemical synthesis
Reverse Transcriptase Inhibitors chemistry
Structure-Activity Relationship
Triazines chemical synthesis
Drug Design
HIV Reverse Transcriptase antagonists & inhibitors
HIV-1 drug effects
Pyrroles chemistry
Reverse Transcriptase Inhibitors pharmacology
Triazines chemistry
Triazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 21
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24119448
- Full Text :
- https://doi.org/10.1016/j.bmc.2013.09.009