4-Amino-7-chloroquinolines: Probing Ligand Efficiency Provides Botulinum Neurotoxin Serotype A Light Chain Inhibitors with Significant Antiprotozoal Activity

作者：Igor Opsenica, Mikloš Tot, Laura Gomba, Jonathan E. Nuss, Richard J. Sciotti, Sina Bavari, James C. Burnett, Bogdan A. Šolaja · 发表于：Journal of Medicinal Chemistry · 年份：2013 · DOI：10.1021/jm4006077 · 被引用次数：25 · 研究领域：Botulinum Toxin and Related Neurological Disorders、Venomous Animal Envenomation and Studies、Signaling Pathways in Disease

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 of 1. Three of the new compounds are more active than 1 against both indications. Metabolically, the new inhibitors are relatively stable and nontoxic. 12, 14, and 15 are more potent BoNT/A LC inhibitors than 1. Additionally, 15 has excellent in vitro antimalarial efficacy, with IC90 values 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 by 1 can be retained/exceeded with less structural complexity. 12, 14, and 15 provide new platforms for the development of more potent dual BoNT/A LC and P.f. inhibitors adhering to generally accepted chemical properties associated with the druggability of synthetic molecules.