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[摘要]：Botulinum neurotoxins (BoNTs) are the deadliest of microbial toxins. The enzyme's zinc(II) metalloprotease, referred to as the light chain (LC) component, inhibits acetylcholine release into neuromuscular junctions, resulting in the disease botulism. Currently, no therapies counter BoNT poisoning postneuronal intoxication; however it is hypothesized that small molecules may be used to inhibit BoNT LC activity in the neuronal cytosol. Herein, we describe the pharmacophore-based design and chemical synthesis of potent [non-zinc(II) chelating] small molecule (nonpeptidic) inhibitors (SMNPIs) of the BoNT serotype-A LC (the most toxic of the BoNT serotype LCs). Specifically the three-dimensional superimpositions of 2-[4-(4-amidinephenoxy)-phenyl]indole-6-amidine-based SMNPI regionisomers [K-i = 0.600 mu M (+/-0.100 mu M)], with a novel lead bis-[3-amide-5-(imidazolino) phenyl]terephthalamide (BAIPT)-based SMNPI [K-i = 8.52 mu M (+/-0.53 mu M)], resulted in a refined four zone pharmacophore. The refined model guided the design of BAIPT-based SMNPIs possessing K-i values = 0.572 (+/-0.041 mu M) and 0.900 mu M (0.078 mu M). |
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