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Title: Computer-aided design, Synthesis and validation of 2-phenylquinazolinone fragments as CDK9 inhibitors with anti-HIV-1 Tat-mediated transcription activity
Authors: Sancineto, Luca ×
Iraci, Nunzio
Massari, Serena
Attanasio, Vanessa
Corazza, Gianmarco
Barreca, Maria Letizia
Sabatini, Stefano
Manfroni, Giuseppe
Avanzi, Nilla Roberta
Cecchetti, Violetta
Pannecouque, Christophe
Marcello, Alessandro
Tabarrini, Oriana #
Issue Date: Dec-2013
Publisher: Wiley - V C H Verlag GmbH & Co. KGaA
Series Title: ChemMedChem vol:8 issue:12 pages:1941-53
Article number: 10.1002/cmdc.201300287
Abstract: The activity of the cyclin-dependent kinase 9 (CDK9) is critical for HIV-1 Tat-mediated transcription and represents a promising target for antiviral therapy. Here we present computational studies that, along with preliminary synthetic efforts, allowed us to identify and characterize a new class of nontoxic anti-CDK9 chemotypes based on the 2-phenylquinazolinone scaffold. Inhibition of CDK9 translated into the ability to interfere selectively with Tat-mediated transactivation of the viral promoter and in the inhibition of HIV-1 reactivation from latently infected cells, with the most potent derivative 37 (2-(4-aminophenyl)-7-chloroquinazolin-4(3H)-one) showing an IC50 value of 4.0 μM. Because the herein reported 2-phenylquinazolinones are merely fragments, they are largely optimizable, paving the way to derivatives with improved potency.
URI: 
ISSN: 1860-7179
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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