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: 0301 basic medicine; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Anti-HIV Agents; Cell Survival; Ribonuclease H; HIV Integrase; Virus Replication; Keto Acids; 3. Good health; Structure-Activity Relationship; 03 medical and health sciences; Cell Line, Tumor; HIV-1; Humans; Pyrroles; Enzyme Inhibitors; HeLa Cells

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.