5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors belonging to the DABO family
| Autor: | Gianluca Sbardella, Silvio Massa, Paolo La Colla, Giovanni Maga, Flavia Marturana, Antonello Mai, Massimo Mura, Chiara Musiu, Rino Ragno, Marino Artico, Alessandra Cadeddu |
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| Rok vydání: | 2005 |
| Předmět: |
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Molecular Alkylation Pyrimidine Anti-HIV Agents Stereochemistry Clinical Biochemistry Pharmaceutical Science Ligands Biochemistry Cell Line Nucleoside Reverse Transcriptase Inhibitor Structure-Activity Relationship chemistry.chemical_compound reverse transcriptase Benzyl Compounds Drug Discovery Side chain hiv-1 mutant strains Humans Structure–activity relationship Molecular Biology Alkyl Amination chemistry.chemical_classification dihydro-alkoxy-benzyl-oxopyrimidines docking hiv-1 Molecular Structure Organic Chemistry Wild type Nucleosides Fluorine HIV Reverse Transcriptase Thymine Pyrimidines chemistry Mutation HIV-1 Reverse Transcriptase Inhibitors Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 13:2065-2077 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2005.01.005 |
| Popis: | 2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones (F(2)-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family and bearing different alkyl- and arylamino side chains at the C(2)-position of the pyrimidine ring were designed as active against wild type (wt) human immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants. Biological evaluation indicated the importance of the further anchor point of compounds 4, 5 into the non-nucleoside binding site (NNBS): newly synthesized compounds were highly active against both wild type and the Y181C HIV-1 strains. In anti-wt HIV-1 assay the potency of amino derivatives did not depend on the size or shape of the C(2)-amino side chain, but it associated with the presence of one or two methyl groups (one at the pyrimidine C(5)-position and the other at the benzylic carbon), being thymine, alpha-methyluracil or alpha-methylthymine derivatives almost equally active in reducing wt HIV-1-induced cytopathogenicity in MT-4 cells. Against the Y181C mutant strain, 2,6-difluorobenzyl-alpha-methylthymine derivatives 4d, 5h'-n' showed the highest potency and selectivity among tested compounds, both a properly sized C(2)-NH side chain and the presence of two methyl groups (at C(5) and benzylic positions) being crucial for high antiviral action. |
| Databáze: | OpenAIRE |
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