Synthesis and biological evaluation of substrate-based inhibitors of 6-phosphogluconate dehydrogenase as potential drugs against African trypanosomiasis

被引：25
作者：
Dardonville, C
Rinaldi, E
Hanau, S
Barrett, MP
Brun, R
Gilbert, IH
机构：
[1] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3XF, S Glam, Wales
[2] Univ Ferrara, Dipartmento Biochim & Biol Mol, I-44100 Ferrara, Italy
[3] Univ Glasgow, Div Infect & Immun, IBLS, Glasgow G12 8QQ, Lanark, Scotland
[4] Swiss Trop Inst, CH-4002 Basel, Switzerland
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2003年 / 11卷 / 14期
基金：
英国工程与自然科学研究理事会; 英国惠康基金;
关键词：
D O I：
10.1016/S0968-0896(03)00191-3
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
The synthesis and biological evaluation of three series of 6-phosphogluconate (6PG) analogues is described. (2R)-2-Methyl-4,5-dideoxy, (2R)-2-methyl-4-deoxy and 2,4- dideoxy analogues of 6PG were tested as inhibitors of 6-phosphogluconate dehydrogenase (6PGDH) from sheep liver and also Trypanosonia brucei where the enzyme is a validated drug target. Among the three series of analogues, seven compounds were found to competitively inhibit 6PGDH from T. brucei and sheep liver enzymes at micromolar concentrations. Six inhibitors belong to the (2R)-2-methyl-4-deoxy series (6, 8, 10, 12, 21, 24) and one is a (2R)-2-methyl-4,5-dideoxy analogue (29b). The 2,4-dideoxy analogues of 6PG did not inhibit both enzymes. The trypanocidal effect of the compounds was also evaluated in vitro against T. brucei rhodesiense as well as other related trypanosomatid parasites (i.e., Trypanosoma cruzi and Leishmania donovani). (C) 2003 Elsevier Science Ltd. All rights reserved.
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页码：3205 / 3214
页数：10
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