Indolylarylsulfones carrying a heterocyclic tail as very potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors

Famiglini, Valeria, La Regina, Giuseppe, Coluccia, Antonio, Pelliccia, Sveva, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Maga, Giovanni, Crespan, Emmanuele, Badia, Roger, Riveira-Muñoz, Eva, Esté, José A., Ferretti, Rosella, Cirilli, Roberto, Zamperini, Claudio, Botta, Maurizio, Schols, Dominique, Limongelli, Vittorio, Agostino, Bruno, Novellino, Ettore and Silvestri, Romano 2014. Indolylarylsulfones carrying a heterocyclic tail as very potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors. Journal of Medicinal Chemistry 57 (23) , pp. 9945-9957. 10.1021/jm5011622

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	30 March 2016
Last Modified:	06 Jan 2024 18:02
URI:	https://orca.cardiff.ac.uk/id/eprint/75235

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