ANTIBACTERIAL ACTIVITY AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF BERBERINE ANALOGS

Analogs of berberine 1 and related compounds were prepared to evaluate structure-activity relationships. Among the 13-alkyl-substituted and the 13-unsubstituted protoberberinium salts, the 13-ethyl-9-ethoxyl ho molog 30, the 13-ethyl analog 29, and the 13-methyl derivative 3 showe d an increase in antibacterial activity against Staphylococcus aureus by eight-, four- and twofold respectively over the parent base berberi ne 1; this is suggestive that steric effects play a significant role i n the antibacterial. activity. Reduction of the protoberberinium salts yielding the tetrahydro derivatives greatly reduced the antibacterial activity. Replacement of methoxyl groups at the C-2 and the C-3 of ri ng A by a methylenedioxy group resulted in increased antibacterial act ivity. These data strongly suggest that the quaternary nitrogen atom s uch as in protoberberinium salts, an alkylsubstituent at C-13, and a m ethylenedioxy function at C-2 and C-3 are required for enhanced activi ty. Tetrahydroprotoberberine alpha-N-metho salts showed higher activit y than tetrahydroprotoberberine hydrochlorides, but appreciably lower activity than protoberberinium salts. The effects of substitution at C -13 and on ring A in the alpha-N-metho salt were similar to those in p rotoberberinium salts. Stereochemical changes of the B/C ring juncture from trans to cis, and of the methyl group at C-13 from alpha to beta , had, respectively, marked and slight effects on the activity. The te sted compounds were less active against Escherichia coli (Gram-negativ e bacterium) and Candida albicans (fungus) than S aureus (Gram-positiv e bacterium).