Exploring the Role of 2-Chloro-6-fluoro Substitution in 2-Alkylthio-6-benzyl-5-alkylpyrimidin-4(3H)-ones: Effects in HIV-1-Infected Cells and in HIV-1 Reverse Transcriptase Enzymes
Por:
Rotili, D, Tarantino, D, Nawrozkij, MB, Babushkin, AS, Botta, G, Marrocco, B, Cirilli, R, Menta, S, Badia, R, Crespan, E, Ballante, F, Ragno, R, Este, JA, Maga, G and Mai, A
Publicada:
26 jun 2014
Resumen:
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.
Filiaciones:
Rotili, D:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy
Tarantino, D:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy
Nawrozkij, MB:
Volgograd State Tech Univ, Volgograd 400131, Russia
Babushkin, AS:
Volgograd State Tech Univ, Volgograd 400131, Russia
Botta, G:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy
Marrocco, B:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy
Cirilli, R:
Ist Super Sanita, Dipartimento Farmaco, I-00161 Rome, Italy
Menta, S:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy
:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, IrsiCaixa, Badalona 08916, Spain
Crespan, E:
CNR, IGM, I-27100 Pavia, Italy
Ballante, F:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Rome Ctr Mol Design, I-00185 Rome, Italy
Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63130 USA
Ragno, R:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Rome Ctr Mol Design, I-00185 Rome, Italy
:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, IrsiCaixa, Badalona 08916, Spain
Maga, G:
CNR, IGM, I-27100 Pavia, Italy
Mai, A:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy
Univ Roma La Sapienza, Ist Pasteur Fdn Cenci Bolognetti, I-00185 Rome, Italy
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