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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2013 Nov 14; Vol. 56 (21), pp. 8588-98. Date of Electronic Publication: 2013 Nov 05. - Publication Year :
- 2013
-
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.
- Subjects :
- Anti-HIV Agents chemical synthesis
Anti-HIV Agents chemistry
Cell Line, Tumor
Cell Survival drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
HeLa Cells
Humans
Keto Acids chemical synthesis
Keto Acids chemistry
Molecular Structure
Pyrroles chemical synthesis
Pyrroles chemistry
Ribonuclease H metabolism
Structure-Activity Relationship
Virus Replication drug effects
Anti-HIV Agents pharmacology
Enzyme Inhibitors pharmacology
HIV Integrase metabolism
HIV-1 drug effects
Keto Acids pharmacology
Pyrroles pharmacology
Ribonuclease H antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 56
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24124919
- Full Text :
- https://doi.org/10.1021/jm401040b