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. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Paola Conti, Andrea Pinto, Pui E Wong, Louise L Major, Lucia Tamborini, Maria C Iannuzzi, Carlo De Micheli, Michael P Barrett, Terry K Smith. Synthesis and in vitro/in vivo evaluation of the antitrypanosomal activity of 3-bromoacivicin, a potent CTP synthetase inhibitor. ChemMedChem. 2011 Feb 7;6(2):329-33

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PMID: 21275056

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