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 homolog 30, the 13-ethyl analog 29, and the 13-methyl derivative 3 showed an increase in antibacterial activity against Staphylococcus aureus by eight-, four- and twofold respectively over the parent base berberine 1; this is suggestive that steric effects play a significant role in 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 ring A by a methylenedioxy group resulted in increased antibacterial activity. These data strongly suggest that the quaternary nitrogen atom such as in protoberberinium salts, an alkylsubstituent at C-13, and a methylenedioxy function at C-2 and C-3 are required for enhanced activity. Tetrahydroprotoberberine α-N-metho salts showed higher activity than tetrahydroprotoberberine hydrochlorides, but appreciably lower activity than protoberberinium salts. The effects of substitution at C-13 and on ring A in the α-N-metho salt were similar to those in protoberberinium salts. Stereochemical changes of the B/C ring juncture from trans to cis, and of the methyl group at C-13 from α to β, had, respectively, marked and slight effects on the activity. The tested compounds were less active against Escherichia coli (Gram-negative bacterium) and Candida albicans (fungus) than S aureus (Gram-positive bacterium).