4-Amino-7-chloroquinolines: probing ligand efficiency provides botulinum neurotoxin serotype A light chain inhibitors with significant antiprotozoal activity.
4-Amino-7-chloroquinolines: probing ligand efficiency provides botulinum neurotoxin serotype A light chain inhibitors with significant antiprotozoal activity.
复制标题
4-氨基-7-氯喹啉：探测配体效率，提供具有显着抗原虫活性的肉毒杆菌神经毒素血清型 A 轻链抑制剂。
DOI：
10.1021/jm4006077
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发表时间：
2013
影响因子：
7.3
通讯作者：
Solaja,BogdanA
中科院分区：
文献类型：
--
作者：
Opsenica,IgorM;Tot,Mikloš;Gomba,Laura;Nuss,JonathanE;Sciotti,RichardJ;Bavari,Sina;Burnett,JamesC;Solaja,BogdanA
制备了双重抗疟和肉毒杆菌神经毒素血清型A轻链（BoNT/A LC）抑制剂双氨基喹啉（1）的结构简化的类似物。设计新的化合物以提高配体效率，同时保持或超过1的抑制效力。其中三种新化合物对两种适应症的活性均高于1种。在代谢上，新的抑制剂是相对稳定和无毒的。12，14和15是比1更有效的BoNT/A LC抑制剂。此外，15具有优异的体外抗疟功效，对5种恶性疟原虫（Plasmodium falciparum，P.f.）菌株：W2、D 6、C235、C2 A和C2B。结果表明，相同水平的抑制效果可以保持/超过1提供较少的结构复杂性。12，14，和15提供了新的平台，开发更有效的双BoNT/A LC和P.f抑制剂坚持普遍接受的化学性质与合成分子的可药用性。
Structurally simplified analogues of dual antimalarial and botulinum neurotoxin serotype A light chain (BoNT/A LC) inhibitor bis-aminoquinoline (1) were prepared. New compounds were designed to improve ligand efficiency while maintaining or exceeding the inhibitory potency of1. Three of the new compounds are more active than1against both indications. Metabolically, the new inhibitors are relatively stable and nontoxic.12,14, and15are more potent BoNT/A LC inhibitors than1. Additionally,15has excellent in vitro antimalarial efficacy, with IC90values ranging from 4.45 to 12.11 nM against five Plasmodium falciparum (P.f.) strains: W2, D6, C235, C2A, and C2B. The results indicate that the same level of inhibitory efficacy provided by1can be retained/exceeded with less structural complexity.12,14, and15provide new platforms for the development of more potent dual BoNT/A LC andP.f.inhibitors adhering to generally accepted chemical properties associated with the druggability of synthetic molecules.