The synthesis and antibacterial activity of totarol derivatives. Part 1: Modifications of ring-c and pro-drugs

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.