1. Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria
- Author
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Richard J. Sciotti, Milica Videnović, Dejan Opsenica, Mario Zlatović, Maja Krstic, Jonathan E. Nuss, Sandra Šegan, Sina Bavari, Života Selaković, Bogdan A. Šolaja, Jelena Konstantinović, Laura Gomba, and James C. Burnett
- Subjects
Stereochemistry ,Plasmodium falciparum ,Drug Resistance ,Chick Embryo ,Immunoglobulin light chain ,01 natural sciences ,Article ,03 medical and health sciences ,Antimalarials ,Structure-Activity Relationship ,Chloroquine ,Drug Discovery ,medicine ,Potency ,Animals ,Humans ,Protease Inhibitors ,Aminoquinolines ,Botulinum Toxins, Type A ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Metalloproteinase ,010405 organic chemistry ,Hep G2 Cells ,In vitro ,3. Good health ,0104 chemical sciences ,Molecular Docking Simulation ,Enzyme ,chemistry ,Docking (molecular) ,Metalloproteases ,Molecular Medicine ,medicine.drug - Abstract
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 mu 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 mu 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' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's 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.
- Published
- 2014