Synthesis and in vitro/in vivo Evaluation of the Antitrypanosomal Activity of 3-Bromoacivicin, a Potent CTP Synthetase Inhibitor

The first convenient synthesis of enantiomerically pure (αS,5S)-α-amino-3-bromo-4,5-dihydroisoxazol-5-yl acetic acid (3-bromoacivicin) is described. We demonstrate that 3-bromoacivicin is a CTP synthetase inhibitor three times as potent as its 3-chloro analogue, the natural antibiotic acivicin. Because CTP synthetase was suggested to be a potential drug target in African trypanosomes, the invitro/invivo antitrypanosomal activity of 3-bromoacivicin was assessed in comparison with acivicin. Beyond expectation, we observed a 12-fold enhancement in the invitro antitrypanosomal activity, while toxicity against mammalian cells remained unaffected. Despite its good invitro activity and selectivity, 3-bromoacivicin proved to be trypanostatic and failed to completely eradicate the infection when tested invivo at its maximum tolerable dose. A tip of the HAT to bromine: The antitrypanosomal activity of the natural antibiotic acivicin can be substantially increased on passing to its 3-bromo analogue. 3-Bromoacivicin is threefold more potent than acivicin as an inhibitor of T.b.brucei CTP synthetase. Interestingly, this translates into a 12-fold increase in the antitrypanosomal activity and a marked improvement in selectivity.