5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3, 4-dihydropyrimidin-4(3H)-ones: novel potent and selective dihydro-alkoxy-benzyl-oxopyrimidine derivatives
| Autor: | P. La Colla, Enzo Tramontano, Silvio Massa, M. E. Marongiu, Gianluca Sbardella, A. G. Loi, Ettore Novellino, Antonello Mai, Giovanni Greco, Marino Artico |
|---|---|
| Přispěvatelé: | Mai, A., Artico, M., Sbardella, G., Massa, S., Novellino, Ettore, Greco, Giovanni, Loi, A. G., DE MONTIS, A., Marongiu, M. E., LA COLLA, P. |
| Rok vydání: | 1999 |
| Předmět: |
Human-Immunodeficiency-Virus
Reverse-Transcriptase inhibitors 3 4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines DABOs Anti-HIV-1 activity Nonnucleoside inhibitors HIV-1 replication Models Molecular Stereochemistry Anti-HIV Agents Cell Survival Substituent Thio Chemical synthesis Cell Line chemistry.chemical_compound Mice Structure-Activity Relationship Pyrimidinones Drug Discovery Animals Alkyl chemistry.chemical_classification HIV Reverse Transcriptase Recombinant Proteins Pyrimidines chemistry 4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines DABOs Drug Design Alkoxy group Lactam Benzyl group HIV-1 Molecular Medicine Reverse Transcriptase Inhibitors |
| Zdroj: | Journal of medicinal chemistry. 42(4) |
| ISSN: | 0022-2623 |
| Popis: | Molecular modeling analysis of compounds belonging to the recently published series of dihydro-alkoxy-benzyl-oxopyrimidines (DABOs), such as S-DABOs and DATNOs, gave support to the design of new 2, 6-disubstituted benzyl-DABO derivatives as highly potent and specific inhibitors of the HIV-1 reverse transcriptase (RT). To follow up on the novel DABO derivatives, we decided to investigate the effect of electron-withdrawing substituents in the benzyl unit of the S-DABO skeleton versus their anti-HIV-1 activity. Such chemical modifications impacted the inhibitory activity, especially when two halogen units were introduced at positions 2 and 6 in the phenyl portion of the benzyl group bound to C-6 of the pyrimidine ring. Various 5-alkyl-2-(alkyl(or cycloalkyl)thio)-6-(2, 6-dichloro(or 2,6-difluoro)phenylmethyl)-3, 4-dihydropyrimidin-4(3H)-ones were then synthesized and tested as anti-HIV-1 agents in both cell-based and enzyme (recombinant reverse transcriptase, rRT) assays. Among the various mono- and disubstituted phenyl derivatives, the most potent were those containing a 6-(2,6-difluorophenylmethyl) substituent (F-DABOs), which showed EC50's ranging between 40 and 90 nM and selectivity indexes up to >/=5000. An excellent correlation was found between EC50 and IC50 values which confirmed that these compounds act as inhibitors of the HIV-1 RT. The structure-activity relationships of the newly synthesized pyrimidinones are presented herein. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|