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Synthesis and Biological Properties of Novel 2-Aminopyrimidin-4(3 H )-ones Highly Potent against HIV-1 Mutant Strains

2007; American Chemical Society; Volume: 50; Issue: 22 Linguagem: Inglês

10.1021/jm070811e

1520-4804

Antonello Mai, Marino Artico, Dante Rotili, Domenico Tarantino, Imma Clotet‐Codina, Mercedes Armand‐Ugón, Rino Ragno, Silvia Simeoni, Gianluca Sbardella, Maxim B. Nawrozkij, Alberta Samuele, Giovanni Maga, José A. Esté,

Tuberculosis Research and Epidemiology

Following the disclosure of dihydro-alkoxy-, dihydro-alkylthio-, and dihydro-alkylamino-benzyl-oxopyrimidines (DABOs, S-DABOs, and NH-DABOs) as potent and selective anti-HIV-1 agents belonging to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, we report here the synthesis and biological evaluation of a novel series of DABOs bearing a N,N-disubstituted amino group or a cyclic amine at the pyrimidine-C2 position, a hydrogen atom or a small alkyl group at C5 and/or at the benzylic position, and the favorable 2,6-difluorobenzyl moiety at the C6 position (F2-N,N-DABOs). The new compounds were highly active up to the subnanomolar level against both wt HIV-1 and the Y181C mutant and at the submicromolar to nanomolar range against the K103N and Y188L mutant strains. Such derivatives were more potent than S-DABOs, NH-DABOs, and nevirapine and efavirenz were chosen as reference drugs. The higher inhibitor adaptability to the HIV-1 RT non-nucleoside binding site (NNBS) may account for the higher inhibitory effect exerted by the new molecules against the mutated RTs.