title: Indolylarylsulfones carrying a heterocyclic tail as very potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors.
abstract: We synthesized new indolylarylsulfone (IAS) derivatives carrying a heterocyclic tail at the indole-2-carboxamide nitrogen as potential anti-HIV/AIDS agents. Several new IASs yielded EC50 values <1.0 nM against HIV-1 WT and mutant strains in MT-4 cells. The (R)-11 enantiomer proved to be exceptionally potent against the whole viral panel; in the reverse transcriptase (RT) screening assay, it was remarkably superior to NVP and EFV and comparable to ETV. The binding poses were consistent with the one previously described for the IAS non-nucleoside reverse transcriptase inhibitors. Docking studies showed that the methyl group of (R)-11 points toward the cleft created by the K103N mutation, different from the corresponding group of (S)-11. By calculating the solvent-accessible surface, we observed that the exposed area of RT in complex with (S)-11 was larger than the area of the (R)-11 complex. Compounds 6 and 16 and enantiomer (R)-11 represent novel robust lead compounds of the IAS class.
authors.affiliation: Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , Piazzale Aldo Moro 5, I-00185 Roma, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Famiglini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
authors.forename: Sveva
authors.initials: S
authors.lastname: Pelliccia
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Roger
authors.initials: R
authors.lastname: Badia
authors.forename: Eva
authors.initials: E
authors.lastname: Riveira-Muñoz
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
authors.forename: Rosella
authors.initials: R
authors.lastname: Ferretti
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.forename: Claudio
authors.initials: C
authors.lastname: Zamperini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.forename: Bruno
authors.initials: B
authors.lastname: Agostino
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D007211:Indoles; D018894:Reverse Transcriptase Inhibitors; D013450:Sulfones