J. Med. Chem., 50 (9), 2127 -2136, 2007. 10.1021/jm061446e S0022-2623(06)01446-4
Web Release Date: April 7, 2007

Copyright © 2007 American Chemical Society

A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

James C. Burnett, Dejan Opsenica, Kamaraj Sriraghavan, Rekha G. Panchal, Gordon Ruthel, Ann R. Hermone, Tam L. Nguyen, Tara A. Kenny, Douglas J. Lane, Connor F. McGrath, James J. Schmidt, Jonathan L. Vennerstrom, Rick Gussio, Bogdan A. olaja,*# and Sina Bavari*

SAIC-Frederick, Inc., Target Structure-Based Drug Discovery Group, Frederick, Frederick, Inc., National Cancer Institute at Frederick, P.O. Box B, F.V.C. 310, Frederick, Maryland 21702, The Institute of Chemistry, Technology, and Metallurgy, Njegoeva 12, YU-11001 Belgrade, Serbia, College of Pharmacy, 986025 University of Nebraska Medical Center, Omaha, Nebraska 68198, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, 1425 Porter Street, Frederick, Maryland 21702, Developmental Therapeutics Program, P.O. Box B, F.V.C. 310, NCI Frederick, Frederick, Maryland 21702, and Faculty of Chemistry, The University of Belgrade, Studentski trg 16, P.O. Box 158, YU-11001 Belgrade, Serbia

Received December 19, 2006

Abstract:

We previously identified structurally diverse small molecule (non-peptidic) inhibitors (SMNPIs) of the botulinum neurotoxin serotype A (BoNT/A) light chain (LC). Of these, several (including antimalarial drugs) contained a 4-amino-7-chloroquinoline (ACQ) substructure and a separate positive ionizable amine component. The same antimalarials have also been found to interfere with BoNT/A translocation into neurons, via pH elevation of the toxin-mediated endosome. Thus, this structural class of small molecules may serve as dual-function BoNT/A inhibitors. In this study, we used a refined pharmacophore for BoNT/A LC inhibition to identify four new, potent inhibitors of this structural class (IC50's ranged from 3.2 to 17 M). Molecular docking indicated that the binding modes for the new SMNPIs are consistent with those of other inhibitors that we have identified, further supporting our structure-based pharmacophore. Finally, structural motifs of the new SMNPIs, as well as two structure-based derivatives, were examined for activity, providing valuable information about pharmacophore component contributions to inhibition.

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