Antiasthmatic acetophenones - an in vivo study on structure activity relationship.

The recently isolated acetophenone glucoside androsin, as the major antiasthmatic principle of Picrorhiza kurroa Royle ex Benth. (Scrophulariaceae), was used as a lead compound for detailed structure-activity relationship studies. More than 25 synthesized or commercially available acetophenones with modified substitution patterns were screened in the Plethysmographic guinea pig model using PAF and/or ovalbumin as challenging agents for the generation of bronchial constriction. Whereas the aglycones in most cases were more effective than the corresponding glycosides, substitution patterns in position 3 and 4 of the phenyl ring and the keto function attached to the phenyl ring were found to be essential for marked antiasthmatic effect. 3,5-Dimethoxy-4-hydroxy-acetophenone (acetosyringenin) showed the highest activity of all tested compounds. Initial in vitro studies on the mode of action could not sufficiently explain the mechanism of antiasthmatic activity.

Wedelolactone and coumestan derivatives as new antihepatotoxic and antiphlogistic principles.

For the study of structure-activity relationships, the antihepatotoxic wedelolactone (7-methoxy-5,11,12-trihydroxy-coumestan) and 6 coumestan derivatives were synthesized by the application of a modified method of Wanzlich. An evaluation of the biological characteristics of the synthetic compounds and acuminatin from Musa acuminata showed that most of the wedelolactone derivatives significantly protected primary cultured liver cells from the toxicity of CCl4, galactosamine (Galc), and phalloidin, and strongly inhibited the activity of 5-lipoxygenase in porcine leukocytes. The hepatocyte protective activity was dependent on the C-7 substitution with pharmacological efficacy decreasing in the following order: EtO greater than MeO greater than OH greater than CH3(CH2)9. In addition, a free OH at C-5 of the wedelolactone molecule was shown to be important in protecting hepatocytes from CCl4 and Galc damage. Similar observation regarding the effect of C-7 substitution in wedelolactone was obtained in the 5-lipoxygenase test. In general, an increase in the lipophilicity in ring A increased the inhibition of 5-lipoxygenase activity. The synthetic wedelolactone was also found to have stimulatory effect on the RNA synthesis in isolated nuclei from hepatocytes.