title: 5-Alkyl-6-benzyl-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones, a series of anti-HIV-1 agents of the dihydro-alkoxy-benzyl-oxopyrimidine family with peculiar structure-activity relationship profile.
abstract: A series of dihydro-alkylthio-benzyl-oxopyrimidines (S-DABOs) bearing a 2-aryl-2-oxoethylsulfanyl chain at pyrimidine C2, an alkyl group at C5, and a 2,6-dichloro-, 2-chloro-6-fluoro-, and 2,6-difluoro-benzyl substitution at C6 (oxophenethyl- S-DABOs, 6-8) is here described. The new compounds showed low micromolar to low nanomolar (in one case subnanomolar) inhibitory activity against wt HIV-1. Against clinically relevant HIV-1 mutants (K103N, Y181C, and Y188L) as well as in enzyme (wt and K103N, Y181I, and L100I mutated RTs) assays, compounds carrying an ethyl/ iso-propyl group at C5 and a 2,6-dichloro-/2-chloro-6-fluoro-benzyl moiety at C6 were the most potent derivatives, also characterized by low fold resistance ratio. Interestingly, the structure-activity relationship (SAR) data drawn from this DABO series are more related to HEPT than to DABO derivatives. These findings were at least in part rationalized by the description of a fair superimposition between the 6-8 and TNK-651 (a HEPT analogue) binding modes in both WT and Y181C RTs.
authors.affiliation: Volgograd State Technical UniVersity, Pr Lenina, 28, 400131 Volgograd, Russia.
authors.forename: Maxim B
authors.initials: MB
authors.lastname: Nawrozkij
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.forename: Domenico
authors.initials: D
authors.lastname: Tarantino
authors.forename: Giorgia
authors.initials: G
authors.lastname: Botta
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Eremiychuk
authors.forename: Ira
authors.initials: I
authors.lastname: Musmuca
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Alberta
authors.initials: A
authors.lastname: Samuele
authors.forename: Samantha
authors.initials: S
authors.lastname: Zanoli
authors.forename: Mercedes
authors.initials: M
authors.lastname: Armand-Ugón
authors.forename: Imma
authors.initials: I
authors.lastname: Clotet-Codina
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Novakov
authors.forename: Boris S
authors.initials: BS
authors.lastname: Orlinson
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
authors.forename: Marino
authors.initials: M
authors.lastname: Artico
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
mesh_terms: D000478:Alkylation; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001554:Benzene / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006859:Hydrogen / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D010100:Oxygen / Q000737:chemistry; D011485:Protein Binding; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D013457:Sulfur Compounds; D006859:Hydrogen; D012194:RNA-Directed DNA Polymerase; D001554:Benzene; D010100:Oxygen