New potent indolylarylsulfone (IAS) HIV-1 NNRTIs were obtained by coupling natural and unnatural amino acids to the 2-carboxamide and introducing different electron-withdrawing substituents at position 4 and 5 of the indole nucleus. The new IASs inhibited the HIV-1 replication in human T-lymphocyte (CEM) cells at low/subnanomolar concentration and were weakly cytostatic. Against the mutant L100I, K103N, and Y181C RT HIV-1 strains in CEM cells, sulfones 3, 4, 19, 27, and 31 were comparable to EFV. The new IASs were inhibitors to Coxsackie B4 virus at low micromolar (2-9 microM) concentrations. Superimposition of PLANTS docked conformations of IASs 19 and 9 revealed different hydrophobic interactions of the 3,5-dimethylphenyl group, for which a staking interaction with Tyr181 aromatic side chain was observed. The binding mode of 19 was not affected by the L100I mutation and was consistent with the interactions reported for the WT strain.
Indolyl Aryl Sulfones bearing Natural and Unnatural Aminoacids. Discovery of Potent Inhibitors of both HIV-1 Non-Nucleoside Wild Type and Resistant Mutant Strains Reverse Transcriptase, and Coxsackie B4 Virus / Piscitelli, Francesco; Coluccia, Antonio; Brancale, A.; LA REGINA, Giuseppe; Sansone, A.; Giordano, C.; Balzarini, J.; Maga, G.; Zanoli, S.; Samuele, A.; Cirilli, R.; LA TORRE, F.; Lavecchia, A.; Novellino, E.; Silvestri, Romano. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 52:(2009), pp. 1922-1934. [10.1021/jm801470b]
Indolyl Aryl Sulfones bearing Natural and Unnatural Aminoacids. Discovery of Potent Inhibitors of both HIV-1 Non-Nucleoside Wild Type and Resistant Mutant Strains Reverse Transcriptase, and Coxsackie B4 Virus.
PISCITELLI, FRANCESCO;COLUCCIA, Antonio;LA REGINA, GIUSEPPE;LA TORRE F.;SILVESTRI, Romano
2009
Abstract
New potent indolylarylsulfone (IAS) HIV-1 NNRTIs were obtained by coupling natural and unnatural amino acids to the 2-carboxamide and introducing different electron-withdrawing substituents at position 4 and 5 of the indole nucleus. The new IASs inhibited the HIV-1 replication in human T-lymphocyte (CEM) cells at low/subnanomolar concentration and were weakly cytostatic. Against the mutant L100I, K103N, and Y181C RT HIV-1 strains in CEM cells, sulfones 3, 4, 19, 27, and 31 were comparable to EFV. The new IASs were inhibitors to Coxsackie B4 virus at low micromolar (2-9 microM) concentrations. Superimposition of PLANTS docked conformations of IASs 19 and 9 revealed different hydrophobic interactions of the 3,5-dimethylphenyl group, for which a staking interaction with Tyr181 aromatic side chain was observed. The binding mode of 19 was not affected by the L100I mutation and was consistent with the interactions reported for the WT strain.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
