Replacement of the Metabolically Labile Methyl Esters in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors with Isoxazolone, Isoxazole, Oxazolone, or Cyano Substituents
- 28 July 2006
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 49 (17) , 5316-5323
- https://doi.org/10.1021/jm060449o
Abstract
The alkenyldiarylmethanes (ADAMs) are a unique class of non-nucleoside reverse transcriptase inhibitors that have potential value in the treatment of HIV/AIDS. However, the potential usefulness of the ADAMs is limited by the presence of metabolically labile methyl ester moieties. A series of novel ADAMs were therefore designed and synthesized in order to replace the metabolically labile methyl ester moieties of the existing ADAM lead compounds with hydrolytically stable, fused isoxazolone, isoxazole, oxazolone, or cyano substituents on the aromatic rings. The methyl ester and methoxy substituents on both of the aromatic rings in the parent compound 1 were successfully replaced with metabolically stable moieties with retention of anti-HIV activity and a general decrease in cytotoxicity.Keywords
This publication has 16 references indexed in Scilit:
- Crystal Structures for HIV-1 Reverse Transcriptase in Complexes with Three Pyridinone Derivatives: A New Class of Non-Nucleoside Inhibitors Effective against a Broad Range of Drug-Resistant StrainsJournal of Medicinal Chemistry, 2005
- Comparison of Ligand-Based and Structure-Based 3D-QSAR Approaches: A Case Study on (Aryl-)Bridged 2-Aminobenzonitriles Inhibiting HIV-1 Reverse TranscriptaseJournal of Medicinal Chemistry, 2005
- Synthesis of Novel Diarylpyrimidine Analogues and Their Antiviral Activity against Human Immunodeficiency Virus Type 1Journal of Medicinal Chemistry, 2004
- Design, Synthesis, and SAR of a Novel Pyrazinone Series with Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitory ActivityJournal of Medicinal Chemistry, 2004
- Structural and biochemical effects of human immunodeficiency virus mutants resistant to non-nucleoside reverse transcriptase inhibitorsThe International Journal of Biochemistry & Cell Biology, 2004
- Non‐Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Past, Present, and FutureChemistry & Biodiversity, 2004
- Structure of unliganded HIV-1 reverse transcriptase at 2.7 å resolution: implications of conformational changes for polymerization and inhibition mechanismsStructure, 1996
- Synthesis and Biological Evaluation of Certain Alkenyldiarylmethanes as Anti-HIV-1 Agents Which Act as Non-Nucleoside Reverse Transcriptase InhibitorsJournal of Medicinal Chemistry, 1996
- Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 å resolutionStructure, 1995
- Crystal Structure at 3.5 Å Resolution of HIV-1 Reverse Transcriptase Complexed with an InhibitorScience, 1992