title: N-Substituted Quinolinonyl Diketo Acid Derivatives as HIV Integrase Strand Transfer Inhibitors and Their Activity against RNase H Function of Reverse Transcriptase.
abstract: Bifunctional quinolinonyl DKA derivatives were first described as nonselective inhibitors of 3'-processing (3'-P) and strand transfer (ST) functions of HIV-1 integrase (IN), while 7-aminosubstituted quinolinonyl derivatives were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonuclease H (RNase H). In this study, we describe the design, synthesis, and biological evaluation of new quinolinonyl diketo acid (DKA) derivatives characterized by variously substituted alkylating groups on the nitrogen atom of the quinolinone ring. Removal of the second DKA branch of bifunctional DKAs, and the amino group in position 7 of quinolinone ring combined with a fine-tuning of the substituents on the benzyl group in position 1 of the quinolinone, increased selectivity for IN ST activity. In vitro, the most potent compound was 11j (IC50 = 10 nM), while the most active compounds against HIV infected cells were ester derivatives 10j and 10l. In general, the activity against RNase H was negligible, with only a few compounds active at concentrations higher than 10 μM. The binding mode of the most potent IN inhibitor 11j within the IN catalytic core domain (CCD) is described as well as its binding mode within the RNase H catalytic site to rationalize its selectivity.
authors.affiliation: †Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P-le Aldo Moro 5, I-00185, Roma, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pescatori
authors.affiliation: ‡Laboratory of Molecular Pharmacology and Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 5068, Bethesda, Maryland 20892-4255, United States.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Métifiot
authors.affiliation: §Resistance Mechanisms Laboratory, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
authors.forename: Suhman
authors.initials: S
authors.lastname: Chung
authors.affiliation: §Resistance Mechanisms Laboratory, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
authors.forename: Takashi
authors.initials: T
authors.lastname: Masoaka
authors.affiliation: †Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P-le Aldo Moro 5, I-00185, Roma, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cuzzucoli Crucitti
authors.affiliation: †Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P-le Aldo Moro 5, I-00185, Roma, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Messore
authors.affiliation: †Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P-le Aldo Moro 5, I-00185, Roma, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pupo
authors.affiliation: †Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P-le Aldo Moro 5, I-00185, Roma, Italy.
authors.forename: Valentina Noemi
authors.initials: VN
authors.lastname: Madia
authors.affiliation: †Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P-le Aldo Moro 5, I-00185, Roma, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Saccoliti
authors.affiliation: †Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P-le Aldo Moro 5, I-00185, Roma, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Scipione
authors.affiliation: †Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P-le Aldo Moro 5, I-00185, Roma, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Tortorella
authors.affiliation: ∥Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.affiliation: ⊥DiSTABiF, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.affiliation: ∥Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.affiliation: ∥Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: §Resistance Mechanisms Laboratory, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
authors.forename: Stuart F J
authors.initials: SF
authors.lastname: Le Grice
authors.affiliation: ‡Laboratory of Molecular Pharmacology and Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 5068, Bethesda, Maryland 20892-4255, United States.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: ‡Laboratory of Molecular Pharmacology and Developmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 5068, Bethesda, Maryland 20892-4255, United States.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.affiliation: †Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P-le Aldo Moro 5, I-00185, Roma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.affiliation: †Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, P-le Aldo Moro 5, I-00185, Roma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
mesh_terms: D020134:Catalytic Domain; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007651:Keto Acids / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry*; D016914:Ribonuclease H / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: C000601373:4-(1-(2,4-difluorophenyl)methyl-4(1H)-quinolinon-3-yl)-2-hydroxy-4-oxo-2-butenoic acid; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D015363:Quinolones; D019427:HIV Integrase; D012194:RNA-Directed DNA Polymerase; D016914:Ribonuclease H; C514801:p31 integrase protein, Human immunodeficiency virus 1