Computer-aided design, Synthesis and validation of 2-phenylquinazolinone fragments as CDK9 inhibitors with anti-HIV-1 Tat-mediated transcription activity
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 #
Wiley - V C H Verlag GmbH & Co. KGaA
ChemMedChem vol:8 issue:12 pages:1941-53
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.