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

Conti, P., Pinto, A., Wong, P.E., Major, L.L., Tamborini, L., Iannuzzi, M.C., De Micheli, C., Barrett, M.P. and Smith, T.K. (2010) Synthesis and in vitro/in vivo Evaluation of the Antitrypanosomal Activity of 3-Bromoacivicin, a Potent CTP Synthetase Inhibitor. ChemMedChem, 6(2), pp. 329-333. (doi:10.1002/cmdc.201000417)

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Publisher's URL: http://dx.doi.org/10.1002/cmdc.201000417

Abstract

The first convenient synthesis of enantiomerically pure (alpha S,5S)-alpha-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 trypano-static and failed to completely eradicate the infection when tested in vivo at its maximum tolerable dose

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Barrett, Professor Michael and Wong, Dr Pui Ee
Authors: Conti, P., Pinto, A., Wong, P.E., Major, L.L., Tamborini, L., Iannuzzi, M.C., De Micheli, C., Barrett, M.P., and Smith, T.K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:ChemMedChem
ISSN:1860-7179

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