title: Computer-aided design, synthesis and validation of 2-phenylquinazolinone fragments as CDK9 inhibitors with anti-HIV-1 Tat-mediated transcription activity.
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.
authors.affiliation: Department of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia (Italy).
authors.forename: Luca
authors.initials: L
authors.lastname: Sancineto
authors.forename: Nunzio
authors.initials: N
authors.lastname: Iraci
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.forename: Vanessa
authors.initials: V
authors.lastname: Attanasio
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Corazza
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.forename: Nilla Roberta
authors.initials: NR
authors.lastname: Avanzi
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marcello
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017076:Computer-Aided Design; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D017434:Protein Structure, Tertiary; D052999:Quinazolinones / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D052999:Quinazolinones; D054322:tat Gene Products, Human Immunodeficiency Virus; D042863:Cyclin-Dependent Kinase 9
keywords: CDK9; P-TEFb; Tat-mediated transcription; antiviral agents; computational chemistry; inhibitors; kinases