Exploring the Role of 2-Chloro-6-fluoro Substitution in 2-Alkylthio-6-benzyl-5-alkylpyrimidin-4(3H)-ones: Effects in HIV-1-Infected Cells and in HIV-1 Reverse Transcriptase Enzymes
| Autor: | Dante Rotili, Antonello Mai, Roger Badia, Alexandre S. Babushkin, Sergio Menta, Giorgia Botta, M. B. Nawrozkij, Roberto Cirilli, Rino Ragno, Biagina Marrocco, José A. Esté, Emmanuele Crespan, Giovanni Maga, Domenico Tarantino, Flavio Ballante |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Anti-HIV Agents Stereochemistry Mutant Human immunodeficiency virus (HIV) Pyrimidinones medicine.disease_cause Cell Line Stereocenter Structure-Activity Relationship Drug Resistance Viral Drug Discovery medicine Humans Biological sciences chemistry.chemical_classification biology Absolute configuration Stereoisomerism HIV Reverse Transcriptase Enzyme assay Reverse transcriptase Enzyme chemistry Mutation HIV-1 biology.protein Reverse Transcriptase Inhibitors Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 57:5212-5225 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm500284x |
| Popis: | A comparison of the effects of the 6-(2-chloro-6-fluorobenzyl)-2-(alkylthio)pyrimidin-4(3H)-ones (2-Cl-6-F-S-DABOs) 7-12 and the related 6-(2,6-difluorobenzyl) counterparts 13-15 in HIV-1 infected cells and in the HIV-1 reverse transcriptase (RT) assays is here described. The new 2-Cl-6-F-S-DABOs showed up to picomolar activity against wt HIV-1. Against clinically relevant HIV-1 mutants and in enzyme assays, the simultaneous C5(methyl)/C6(methyl/ethyl) substitution in the 2-Cl-6-F- and 2,6-F2-benzyl series furnished compounds with the highest, wide-spectrum inhibitory activity against HIV-1. Three representative 2-Cl-6-F-S-DABOs carrying two (9c, 10c) or one (10a) stereogenic centers were resolved into their individual stereoisomers and showed a significant diastereo- and enantioselectivity in HIV-1 inhibition, the highest antiviral activity well correlating with the R absolute configuration to the stereogenic center of the C6-benzylic position in both cellular and enzymatic tests. Application of previously reported COMBINEr protocol on 9c and 10c confirmed the influence of the stereogenic centers on their binding modes in the HIV-1 RT. |
| Databáze: | OpenAIRE |
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