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 mm. Because the herein reported 2-phenylquinazolinones are merely fragments, they are largely optimizable, paving the way to derivatives with improved potency.

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;BARRECA, MARIA LETIZIA;SABATINI, STEFANO;MANFRONI, GIUSEPPE;CECCHETTI, Violetta;TABARRINI, Oriana
2013

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 mm. Because the herein reported 2-phenylquinazolinones are merely fragments, they are largely optimizable, paving the way to derivatives with improved potency.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1152672
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