Thiotetrazole alkynylacetanilides as potent and bioavailable non-nucleoside inhibitors of the HIV-1 wild type and K103N/Y181C double mutant reverse transcriptases

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 16; pp. 4437 - 4441
• Main Authors: Gagnon, Alexandre, Amad, Ma’an H., Bonneau, Pierre R., Coulombe, René, DeRoy, Patrick L., Doyon, Louise, Duan, Jianmin, Garneau, Michel, Guse, Ingrid, Jakalian, Araz, Jolicoeur, Eric, Landry, Serge, Malenfant, Eric, Simoneau, Bruno, Yoakim, Christiane
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-08-2007; Elsevier
• Subjects: Acetanilides - chemistry; Acetanilides - pharmacology; Alkynes; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Biological Availability; Double mutant reverse transcriptase; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus 1; Medical sciences; Models, Molecular; Molecular modeling; Molecular Structure; Mutation; Non-nucleoside reverse transcriptase inhibitor (NNRTI); Pharmacokinetics; Pharmacology. Drug treatments; Rats; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; SAR; Structure-Activity Relationship; Thiotetrazoles; Thiotetrazoles; SAR; Molecular modeling; Pharmacokinetics; Double mutant reverse transcriptase; Alkynes; Non-nucleoside reverse transcriptase inhibitor (NNRTI); Tetrazole derivatives; Cyclopropane derivatives; RNA-directed DNA polymerase; Intravenous administration; Acetylenic compound; Rat; HIV-1 virus; Non nucleoside compound; Modeling; Structure activity relation; Chlorine Organic compounds; Reverse transcriptase inhibitor; Molecular model; Antiviral; Chemical synthesis; Enzyme; Transferases; Rodentia; Oral administration; Retroviridae; Enzyme inhibitor; Aniline derivatives; Bioavailability; Lentivirus; Virus; Nucleotidyltransferases; Vertebrata; Mammalia; Animal; Human immunodeficiency virus; Mutation; Alkyne; Aromatic amine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.06.012

The SAR and PK studies of a series of thiotetrazolyl akynylacetanilides as potent inhibitors of the HIV-1 RT is reported.
A series of aryl thiotetrazolylacetanilides were synthesized and found to be potent inhibitors of the HIV-1 wild type and K103N/Y181C double mutant reverse transcriptases. The incorporation of an alkynyl fragment on the aniline provided inhibitors with excellent cellular activity and extensive SAR led to the identification of one inhibitor having good oral bioavailability in rats.