Open Access6-(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
Author(s) -
Roberta Costi,
Mathieu Métifiot,
Francesca Esposito,
Giuliana Cuzzucoli Crucitti,
Luca Pescatori,
Antonella Messore,
Luigi Scipione,
Silvano Tortorella,
Luca Zinzula,
Ettore Novellino,
Yves Pommier,
Enzo Tramontano,
Christophe Marchand,
Roberto Di Santo
Publication year - 2013
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm401040b
Subject(s) - integrase , chemistry , rnase h , reverse transcriptase , integrase inhibitor , stereochemistry , moiety , ic50 , enzyme , in vitro , biochemistry , human immunodeficiency virus (hiv) , virology , rna , dna , biology , antiretroviral therapy , viral load , gene
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.