A series of analogues of, and potential
pro-drugs derived from, the potent antibacterial
diterpene totarol (1) were synthesized in order to elucidate the minimum structural requirements for antibacterial activity and to seek compounds with good bioavailability in vivo. These analogues varied in the structural features of their aromatic rings and the
prodrugs were O-glycosylated derivatives. They were tested in vitro against three gram-positive bacteria:
beta-lactamase-positive and high level
gentamycin-resistant Enterococcus faecalis,
penicillin-resistant Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus (MRSA); and against the gram-negative multi-
drug-resistant Klebsiella pneumoniae. None of the analogues was more potent than
totarol itself, which is effective against these gram-positive bacteria at MIC values of 7 microM. The results were evaluated in terms of a structure-activity relationship and this showed that a phenolic moiety was essential for potent antibacterial activity. Amongst the
pro-drugs, totaryl alpha-D-
mannopyranoside (22) proved the most active in vitro (MIC 18 microM). The in vivo antibacterial activities of compounds 1, 22 and
totarol beta-lactoside (23) were assessed in a mouse model of
infection, but they were found to be ineffective. Compounds 1 and 22 were shown to be cytotoxic towards proliferating human cell cultures, CH 2983, HeLa, and MG 63, but only at concentrations of > 30 microM.