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
Por:
Nawrozkij, MB, Rotili, D, Tarantino, D, Botta, G, Eremiychuk, AS, Musmuca, I, Ragno, R, Samuele, A, Zanoli, S, Armand-Ugon, M, Clotet-Codina, I, Novakov, IA, Orlinson, BS, Maga, G, Este, JA, Artico, M and Mai, A
Publicada:
14 ago 2008
Resumen:
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 L1001 mutated RTs) assays, compounds carrying an ethylliso-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.
Filiaciones:
Nawrozkij, MB:
Volgograd State Tech Univ, Volgograd 400131, Russia
Rotili, D:
Univ Roma La Sapienza, Dipartimento Studi Farmaceut, I-00185 Rome, Italy
Tarantino, D:
Univ Roma La Sapienza, Dipartimento Studi Farmaceut, I-00185 Rome, Italy
Botta, G:
Univ Roma La Sapienza, Dipartimento Studi Farmaceut, I-00185 Rome, Italy
Eremiychuk, AS:
Volgograd State Tech Univ, Volgograd 400131, Russia
Musmuca, I:
Univ Roma La Sapienza, Dipartimento Studi Farmaceut, I-00185 Rome, Italy
Ragno, R:
Univ Roma La Sapienza, Dipartimento Studi Farmaceut, I-00185 Rome, Italy
Samuele, A:
IGM CNR, I-27100 Pavia, Italy
Zanoli, S:
IGM CNR, I-27100 Pavia, Italy
Armand-Ugon, M:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, Retrovirol Lab IrsiCaixa, Badalona 08916, Spain
Clotet-Codina, I:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, Retrovirol Lab IrsiCaixa, Badalona 08916, Spain
Novakov, IA:
Volgograd State Tech Univ, Volgograd 400131, Russia
Orlinson, BS:
Volgograd State Tech Univ, Volgograd 400131, Russia
Maga, G:
IGM CNR, I-27100 Pavia, Italy
:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, Retrovirol Lab IrsiCaixa, Badalona 08916, Spain
Artico, M:
Univ Roma La Sapienza, Dipartimento Studi Farmaceut, I-00185 Rome, Italy
Mai, A:
Univ Roma La Sapienza, Dipartimento Studi Farmaceut, I-00185 Rome, Italy
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