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

• Published in: Journal of medicinal chemistry Vol. 51; no. 15; pp. 4641 - 4652
• Main Authors: Nawrozkij, Maxim B, Rotili, Dante, Tarantino, Domenico, Botta, Giorgia, Eremiychuk, Alexandre S, Musmuca, Ira, Ragno, Rino, Samuele, Alberta, Zanoli, Samantha, Armand-Ugón, Mercedes, Clotet-Codina, Imma, Novakov, Ivan A, Orlinson, Boris S, Maga, Giovanni, Esté, José A, Artico, Marino, Mai, Antonello
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.08.2008; Amer Chemical Soc
• Subjects: Alkylation; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Benzene - chemistry; Chemical Phenomena; Chemistry, Medicinal; Chemistry, Physical; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Hydrogen - chemistry; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Mutation - genetics; Oxygen - chemistry; Pharmacology & Pharmacy; Protein Binding; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; RNA-Directed DNA Polymerase - genetics; RNA-Directed DNA Polymerase - metabolism; Science & Technology; Structure-Activity Relationship; Sulfur Compounds - chemical synthesis; Sulfur Compounds - chemistry; Sulfur Compounds - pharmacology; S-DABO DERIVATIVES; NONNUCLEOSIDE INHIBITORS; IN-VITRO; 3,4-DIHYDRO-2-ALKOXY-6-BENZYL-4-OXOPYRIMIDINES DABOS; SOURCE JAVA LIBRARY; DEVELOPMENT KIT CDK; IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIVIRAL ACTIVITY; HIV-1 REVERSE-TRANSCRIPTASE; PROTEIN DATA-BANK
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800340w

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.