Cyclic Variations of 3-Quinolinecarboxamides and Effects on Antiherpetic Activity

• Published in: Journal of medicinal chemistry Vol. 38; no. 14; pp. 2541 - 2545
• Main Authors: Wentland, Mark P, Carlson, John A, Dorff, Peter H, Aldous, Suzanne C, Perni, Robert B, Young, Dorothy C, Woods, Maureen G, Kingsley, Susan D, Ryan, Kathryn A, Rosi, David, Drozd, Marion L, Dutko, Frank J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-07-1995
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Disease Models, Animal; Herpes Genitalis - drug therapy; Herpesvirus 2, Human - drug effects; Herpesvirus 2, Human - growth & development; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Pharmacology. Drug treatments; Quinolines - chemistry; Quinolines - pharmacology; Viral Plaque Assay; Nitrogen heterocycle; Herpesviridae; Alphaherpesvirinae; Rodentia; Oral administration; Herpes; Quinoline derivatives; Tricyclic compound; In vitro; Infection; Virus; In vivo; Vertebrata; Mammalia; Structure activity relation; Mouse; Herpesvirus hominis 2; Viral disease; Animal; Antiviral; Aromatic compound; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00014a006

Supported by the antiherpetic properties of 3-quinolinecarboxamides and the importance of the planar intramolecular H-bonded beta-keto amide pharmacophore, a series of novel conformationally rigid analogues that contain a heterocyclic bridge between the 3- and 4-positions of the quinoline ring have been evaluated. Two isoxazolo-fused derivatives 17 and 23 displayed good in vitro antiherpetic potency that was similar to that of 1, the 3-quinolinecarboxamide that served as the comparison structure for this study. The pyrazolo, pyrrolo, and pyrimido derivatives showed considerably less or no activity. In vitro activity did not translate to in vivo efficacy. For 17, the lack of in vivo activity is likely a consequence of insufficient plasma drug levels (both Cmax and duration) in mice relative to the MIC versus HSV-2.