Gb. Evans et al., The synthesis and antibacterial activity of totarol derivatives. Part 1: Modifications of ring-c and pro-drugs, BIO MED CH, 7(9), 1999, pp. 1953-1964
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-glycosy
lated derivatives. They were tested in vitro against three Gram-positive ba
cteria: beta-lactamase-positive and high level gentamycin-resistant Enteroc
occus faecalis, penicillin-resistant Streptococcus pneumoniae, and methicil
lin-resistant Staphylococcus aureus (MRSA); and against the Cram-negative m
ulti-drug-resistant Klebsiella pneumoniae. None of the analogues was more p
otent than totarol itself, which is effective against these Gram-positive b
acteria at MIC values of 7 mu M. The results were evaluated in terms of a s
tructure-activity relationship and this showed that a phenolic moiety was e
ssential for potent antibacterial activity. Amongst the pro-drugs, totaryl
alpha-D-mannopyranoside (22) proved the most active in vitro (MIC 18 mu M).
The in vivo antibacterial activities of compounds 1, 22 and totarol beta-l
actoside (23) were assessed in a mouse model of infection, but they were fo
und to be ineffective. Compounds 1 and 22 were shown to be cytotoxic toward
s proliferating human cell cultures, CH 2983, HeLa, and MG 63, but only at
concentrations of > 30 mu M. (C) 1999 Elsevier Science Ltd. All rights rese
rved.