Discovery of Covalent Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase, A Target for the Treatment of Malaria

被引：44

作者：

Bruno, Stefano ^{[1
,2
,5
]}

Pinto, Andrea ^{[3
]}

Paredi, Gianluca ^{[1
,2
]}

Tamborini, Lucia ^{[3
]}

De Micheli, Carlo ^{[3
]}

La Pietra, Valeria ^{[4
]}

Marinelli, Luciana ^{[4
]}

Novellino, Ettore ^{[4
]}

Conti, Paola ^{[3
]}

Mozzarelli, Andrea ^{[1
,2
,6
]}

机构：

[1] Univ Parma, Dipartimento Farm, I-43124 Parma, Italy

[2] Univ Parma, Ctr Siteia Parma, I-43124 Parma, Italy

[3] Univ Milan, Dipartimento Sci Farmaceut, I-20133 Milan, Italy

[4] Univ Naples Federico II, Dipartimento Farm, I-80138 Naples, Italy

[5] CNR, Ist Biosci & Biorisorse, I-80131 Naples, Italy

[6] Ist Nazl Biostrutture & Biosistemi, I-00136 Rome, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 17期

关键词：

BACILLUS-STEAROTHERMOPHILUS; TRYPANOSOMA-BRUCEI; INACTIVATION; MECHANISM; CRYSTAL; ACID;

D O I：

10.1021/jm500747h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We developed a new class of covalent inhibitors of Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase, a validated target for the treatment of malaria, by screening a small library of 3-bromo-isoxazoline derivatives that inactivate the enzyme through a covalent, selective bond to the catalytic cysteine, as demonstrated by mass spectrometry. Substituents on the isoxazolinic ring modulated the potency up to 20-fold, predominantly due to an electrostatic effect, as assessed by computational analysis.

引用

页码：7465 / 7471

页数：7

共 35 条

[1]

[Anonymous], 2011, MAESTR V 9 2 112

[2]

[Anonymous], 2011, PRIM V 3 0

[3]

[Anonymous], 2011, JAG V 7 8

[4] Toward the Development of Dual-Targeted Glyceraldehyde-3-phosphate Dehydrogenase/Trypanothione Reductase Inhibitors against Trypanosoma brucei and Trypanosoma cruzi [J].