Exploring the role of 2-chloro-6-fluoro substitution in 2-alkylthio-6-benzyl-5-alkylpyrimidin-4(3 H)-ones: Effects in HIV-1-infected cells and in HIV-1 reverse transcriptase enzymes

Dante Rotili, Domenico Tarantino, Maxim B. Nawrozkij, Alexandre S. Babushkin, Giorgia Botta, Biagina Marrocco, Roberto Cirilli, Sergio Menta, Roger Badia, Emmanuele Crespan, Flavio Ballante, Rino Ragno, José A. Esté, Giovanni Maga, Antonello Mai

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16 Citations (Scopus)

Abstract

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-F 2-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. © 2014 American Chemical Society.
Original languageEnglish
Pages (from-to)5212-5225
JournalJournal of Medicinal Chemistry
Volume57
Issue number12
DOIs
Publication statusPublished - 26 Jun 2014

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