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.
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.
Nawrozkij
Maxim B
MB
Volgograd State Technical UniVersity, Pr Lenina, 28, 400131 Volgograd, Russia.
Rotili
Dante
D
Tarantino
Domenico
D
Botta
Giorgia
G
Eremiychuk
Alexandre S
AS
Musmuca
Ira
I
Ragno
Rino
R
Samuele
Alberta
A
Zanoli
Samantha
S
Armand-Ugón
Mercedes
M
Clotet-Codina
Imma
I
Novakov
Ivan A
IA
Orlinson
Boris S
BS
Maga
Giovanni
G
Esté
José A
JA
Artico
Marino
M
Mai
Antonello
A
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*
D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D013457:Sulfur Compounds; D006859:Hydrogen; D012194:RNA-Directed DNA Polymerase; D001554:Benzene; D010100:Oxygen