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 Rela

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• 作者：Maxim B. Nawrozkij ; Dante Rotili ; Domenico Tarantino ; Giorgia Botta ; Alexandre S. Eremiychuk ; Ira Musmuca ; Rino Ragno ; Alberta Samuele ; Samantha Zanoli ; Mercedes Armand-Ugó ; n ; Imma Clotet-Codina
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：August 14, 2008
• 年：2008
• 卷：51
• 期：15
• 页码：4641-4652
• 全文大小：315K
• 年卷期：v.51,no.15(August 14, 2008)
• ISSN：1520-4804

文摘

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.