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

被引：37

作者：

Conti, Paola ^{[1
]}

Pinto, Andrea ^{[1
]}

Wong, Pui E. ^{[2
]}

Major, Louise L. ^{[3
]}

Tamborini, Lucia ^{[1
]}

Iannuzzi, Maria C. ^{[1
]}

De Micheli, Carlo ^{[1
]}

Barrett, Michael P. ^{[2
]}

Smith, Terry K. ^{[3
]}

机构：

[1] Univ Milan, Dipartimento Sci Farmaceut P Pratesi, I-20133 Milan, Italy

[2] Univ Glasgow, Coll Med Vet & Life Sci, Inst Infect Immun & Inflammat, Wellcome Trust Ctr Mol Parasitol, Glasgow G12 8TA, Lanark, Scotland

[3] Univ St Andrews, Ctr Biomol Sci, St Andrews KY16 9ST, Fife, Scotland

来源：

CHEMMEDCHEM | 2011年 / 6卷 / 02期

基金：

英国惠康基金;

关键词：

amino acids; CTP synthetase; inhibitors; transferases; trypanosoma; AFRICAN SLEEPING SICKNESS; ACIVICIN; ACID;

D O I：

10.1002/cmdc.201000417

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：329 / 333

页数：5

共 15 条

[1] Human African trypanosomiasis [J].