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 in vitro/in vivo antitrypanosomal activity of 3‐bromoacivicin was assessed in comparison with acivicin. Beyond expectation, we observed a 12‐fold enhancement in the in vitro antitrypanosomal activity, while toxicity against mammalian cells remained unaffected. Despite its good in vitro activity and selectivity, 3‐bromoacivicin proved to be trypanostatic and failed to completely eradicate the infection when tested in vivo 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.