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5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones: Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives

Mai, Antonello ; Artico, Marino ; Sbardella, Gianluca ; Massa, Silvio ; Novellino, Ettore ; Greco, Giovanni ; Loi, Anna Giulia ; Tramontano, Enzo ; Marongiu, Maria Elena ; La Colla, Paolo

Journal of medicinal chemistry, 1999-02, Vol.42 (4), p.619-627 [Periódico revisado por pares]

Washington, DC: American Chemical Society

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5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones: Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives
Autor: Mai, Antonello ; Artico, Marino ; Sbardella, Gianluca ; Massa, Silvio ; Novellino, Ettore ; Greco, Giovanni ; Loi, Anna Giulia ; Tramontano, Enzo ; Marongiu, Maria Elena ; La Colla, Paolo
Assuntos: AIDS/HIV ; Animals ; Anti-HIV Agents - chemical synthesis ; Anti-HIV Agents - chemistry ; Anti-HIV Agents - pharmacology ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Biological and medical sciences ; Cell Line ; Cell Survival - drug effects ; Drug Design ; HIV Reverse Transcriptase - antagonists & inhibitors ; HIV-1 - drug effects ; Medical sciences ; Mice ; Models, Molecular ; Pharmacology. Drug treatments ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Recombinant Proteins - antagonists & inhibitors ; Reverse Transcriptase Inhibitors - chemical synthesis ; Reverse Transcriptase Inhibitors - chemistry ; Reverse Transcriptase Inhibitors - pharmacology ; Structure-Activity Relationship
É parte de: Journal of medicinal chemistry, 1999-02, Vol.42 (4), p.619-627
Notas: ark:/67375/TPS-9MQK0N5B-3
istex:64581EA64A6612E4E2F114B664F2E10D609D800C
ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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.
Editor: Washington, DC: American Chemical Society
Idioma: Inglês

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5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones: Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives

Mai, Antonello ; Artico, Marino ; Sbardella, Gianluca ; Massa, Silvio ; Novellino, Ettore ; Greco, Giovanni ; Loi, Anna Giulia ; Tramontano, Enzo ; Marongiu, Maria Elena ; La Colla, Paolo

Washington, DC: American Chemical Society

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