title: 6-(1-Benzyl-1H-pyrrol-2-yl)-2,4-dioxo-5-hexenoic acids as dual inhibitors of recombinant HIV-1 integrase and ribonuclease H, synthesized by a parallel synthesis approach.
abstract: The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug-drug interactions warrant the development of new anti-HIV agents. We previously discovered hit 6, active against HIV-1 replication and targeting RNase H in vitro. Because of its diketo-acid moiety, we speculated that this chemotype could serve to develop dual inhibitors of both RNase H and integrase. Here, we describe a new series of 1-benzyl-pyrrolyl diketohexenoic derivatives, 7a-y and 8a-y, synthesized following a parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase H and integrase) and in cell-based assays. Approximately half (22) exibited inhibition of HIV replication. Compounds 7b, 7u, and 8g were the most active against the RNase H activity of reverse-transcriptase, with IC50 values of 3, 3, and 2.5 μM, respectively. Compound 8g was also the most potent integrase inhibitor with an IC50 value of 26 nM.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma , P. le Aldo Moro 5, Rome I-00185, Italy .
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.forename: Mathieu
authors.initials: M
authors.lastname: Métifiot
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cuzzucoli Crucitti
authors.forename: Luca
authors.initials: L
authors.lastname: Pescatori
authors.forename: Antonella
authors.initials: A
authors.lastname: Messore
authors.forename: Luigi
authors.initials: L
authors.lastname: Scipione
authors.forename: Silvano
authors.initials: S
authors.lastname: Tortorella
authors.forename: Luca
authors.initials: L
authors.lastname: Zinzula
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019427:HIV Integrase / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016914:Ribonuclease H / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: C587005:6-(1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)-2,4-dioxo-5-hexenoic acid; D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D007651:Keto Acids; D011758:Pyrroles; D019427:HIV Integrase; D016914:Ribonuclease H; C514801:p31 integrase protein, Human immunodeficiency virus 1