3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3
3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3
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DOI：
10.1021/jm301575n
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发表时间：
2013-01-10
影响因子：
7.3
通讯作者：
Kunick, Conrad
中科院分区：
文献类型：
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作者：
Fugel, Wiebke;Oberholzer, Anselm Erich;Kunick, Conrad
恶性疟原虫是引起热带疟疾的传染源。寄生虫糖原合成酶激酶-3（Pf GSK-3）被认为是新型抗疟药物的潜在生物靶点。从高通量筛选活动中鉴定的命中结构开始，发现3，6-二氨基-4-（2-卤代苯基）-2-苯甲酰基噻吩并[2，3-B]吡啶-5-腈作为一类新的Pf GSK-3抑制剂。标题化合物对其他物种的GSK-3同系物的活性较低，对Pf GSK-3表现出较好的选择性。考虑到与人GSK-3（HsGSK-3）复合的相关分子的X射线结构，计算了用于与疟原虫和人酶的抑制剂复合物的比较的模型。发现ATP结合口袋中的细微差异是观察到的Pf GSK-3与HsGSK-3选择性的原因。标题化合物类的代表显示出对恶性疟原虫红细胞期寄生虫的微摩尔IC 50值。这些结果表明，Pf GSK-3抑制剂可作为潜在的抗疟药物开发。
Plasmodium falciparum is the infective agent responsible for malaria tropica. The glycogen synthase kinase-3 of the parasite (Pf GSK-3) was suggested as a potential biological target for novel antimalarial drugs. Starting from hit structures identified in a high-throughput screening campaign, 3,6-diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles were discovered as a new class of Pf GSK-3 inhibitors. Being less active on GSK-3 homologues of other species, the title compounds showed selectivity in favor of Pf GSK-3. Taking into account the Xray structure of a related molecule in complex with human GSK-3 (HsGSK-3), a model was computed for the comparison of inhibitor complexes with the plasmodial and human enzymes. It was found that subtle differences in the ATP-binding pockets are responsible for the observed Pf GSK-3 vs HsGSK-3 selectivity. Representatives of the title compound class exhibited micromolar IC50 values against P. falciparum erythrocyte stage parasites. These results suggest that inhibitors of Pf GSK-3 could be developed as potential antimalarial drugs.