Chiral indolylarylsulfone non-nucleoside reverse transcriptase inhibitors as new potent and broad spectrum anti-HIV-1 agents

Famiglini, Valeria, La Regina, Giuseppe, Coluccia, Antonio, Masci, Domiziana, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Badia, Roger, Riveira Muñoz, Eva, Este, Jose A., Crespan, Emmanuele, Brambilla, Alessandro, Maga, Giovanni, Catalano, Myriam, Limatola, Cristina, Formica, Francesca Romana Romana, Cirilli, Roberto, Novellino, Ettore and Silvestri, Romano 2017. Chiral indolylarylsulfone non-nucleoside reverse transcriptase inhibitors as new potent and broad spectrum anti-HIV-1 agents. Journal of Medicinal Chemistry 60 (15) , pp. 6528-6547. 10.1021/acs.jmedchem.6b01906

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Abstract

We designed and synthesized a series of chiral indolyarylsulfones (IASs) as new HIV-1 NNRTIs. The new IASs 8–37 showed potent inhibition of the HIV-1 WT NL4-3 strain and of the mutant K103N, Y181C, Y188L, and K103N–Y181C HIV-1 strains. Six racemic mixtures, 8, 23–25, 31, and 33, were separated at semipreparative level into their pure enantiomers. The (R)-8 enantiomer bearing the chiral (α-methylbenzyl) was superior to the (S)-counterpart. IAS derivatives bearing the (S) alanine unit, (S)-23, (S,R)-25, (S)-31, and (S)-33, were remarkably more potent than the corresponding (R)-enantiomers. Compound 23 protected hippocampal neuronal cells from the excitotoxic insult, while efavirenz (EFV) did not contrast the neurotoxic effect of glutamate. The present results highlight the chiral IASs as new NNRTIs with improved resistance profile against the mutant HIV-1 strains and reduced neurotoxic effects.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RS Pharmacy and materia medica
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	27 June 2017
Date of Acceptance:	19 June 2017
Last Modified:	05 Jan 2024 17:15
URI:	https://orca.cardiff.ac.uk/id/eprint/101791

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