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Design, synthesis, and biological evaluation of anti-HIV double-drugs. conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor through spontaneously cleavable linkers.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2001 Jun; Vol. 9 (6), pp. 1589-600. - Publication Year :
- 2001
-
Abstract
- Based on the prodrug concept as well as the combination of two different classes of anti-HIV agents, we designed and synthesized a series of anti-HIV double-drugs consisting of HIV protease inhibitors conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoins the two different classes of inhibitors has been investigated. Double-drugs using a succinyl amino acid linker were shown to release the parent drugs via spontaneous imide formation at a faster rate compared to compounds using a glutaryl amino acid linker, as expected from the energetically favorable cyclization to the five-membered ring. Among the double-drugs, KNI-1039 (3b) with a glutarylglycine linker exhibited extremely potent anti-HIV activity compared with that of the individual components. Double-drug 3b was relatively stable in culture medium, whereas it regenerated active species in cell homogenate. These results suggested that the synergistic enhancement of anti-HIV activities of 3b may be due to their ability to penetrate into the target cell and subsequent regeneration of two different classes of anti-HIV agents in the cytoplasm.
- Subjects :
- Animals
Anti-HIV Agents chemical synthesis
Drug Design
Drug Evaluation, Preclinical methods
HIV Protease Inhibitors chemical synthesis
Humans
Prodrugs chemistry
Prodrugs pharmacology
Reverse Transcriptase Inhibitors chemical synthesis
Structure-Activity Relationship
Thiazoles chemistry
Thiazoles pharmacology
Tumor Cells, Cultured virology
Zidovudine chemistry
Zidovudine pharmacology
Anti-HIV Agents chemistry
Anti-HIV Agents pharmacology
HIV Protease Inhibitors chemistry
HIV Protease Inhibitors pharmacology
Reverse Transcriptase Inhibitors chemistry
Reverse Transcriptase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0968-0896
- Volume :
- 9
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11408178
- Full Text :
- https://doi.org/10.1016/s0968-0896(01)00045-1