title: 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.
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-F2-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.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma "La Sapienza" , P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.forename: Domenico
authors.initials: D
authors.lastname: Tarantino
authors.forename: Maxim B
authors.initials: MB
authors.lastname: Nawrozkij
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Babushkin
authors.forename: Giorgia
authors.initials: G
authors.lastname: Botta
authors.forename: Biagina
authors.initials: B
authors.lastname: Marrocco
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.forename: Sergio
authors.initials: S
authors.lastname: Menta
authors.forename: Roger
authors.initials: R
authors.lastname: Badia
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Flavio
authors.initials: F
authors.lastname: Ballante
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase