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

• DOI: 10.1021/jm401040b
• Publication Date: 2013-10-14T17:19:16Z
• Authors: Roberta Costi; Mathieu Métifiot; Francesca Esposito; Giuliana Cuzzucol...; Luca Pescatori; Antonella Messore; Luigi Scipione; Silvano Tortorella; Luca Zinzula; Ettore Novellino; Yves Pommier; Enzo Tramontano; Christophe Marchand; Roberto Di Santo
• Keywords: Integrase inhibitor

The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug–drug interactions warrant the development new anti-HIV agents. We previously discovered hit 6, active against HIV-1 replication targeting RNase H in vitro. Because its diketo-acid moiety, we speculated that this chemotype could serve develop dual inhibitors both integrase. Here, describe series 1-benzyl-pyrrolyl diketohexenoic derivatives, 7a–y 8a–y, synthesized following parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase integrase) cell-based assays. Approximately half (22) exibited inhibition HIV replication. Compounds 7b, 7u, 8g were most activity reverse-transcriptase, with IC50 values 3, 2.5 μM, respectively. Compound was also potent integrase inhibitor an value 26 nM.