Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria

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• 作者：Milica Videnovi膰 ; Dejan M. Opsenica ; James C. Burnett ; Laura Gomba ; Jonathan E. Nuss ; 沤ivota Selakovi膰 ; Jelena Konstantinovi膰 ; Maja Krsti膰 ; Sandra 艩egan ; Mario Zlatovi膰 ; Richard J. Sciotti ; Sina Bavari ; Bogdan A. 艩olaja
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4134-4153
• 全文大小：821K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC₅₀ values for such derivatives ranged from 0.81 to 2.27 渭M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K_i of compound 67 is 0.10 渭M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds鈥?in vitro potencies. In addition to specific residue contacts, coordination of the enzyme鈥檚 catalytic zinc and expulsion of the enzyme鈥檚 catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC₉₀ activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.