title: Synthesis and in vitro/in vivo evaluation of the antitrypanosomal activity of 3-bromoacivicin, a potent CTP synthetase inhibitor.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche P. Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. paola.conti@unimi.it
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.forename: Pui E
authors.initials: PE
authors.lastname: Wong
authors.forename: Louise L
authors.initials: LL
authors.lastname: Major
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.forename: Maria C
authors.initials: MC
authors.lastname: Iannuzzi
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
mesh_terms: D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: C557746:3-bromoacivicin; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase