title: Second generation steroidal 4-aminoquinolines are potent, dual-target inhibitors of the botulinum neurotoxin serotype A metalloprotease and P. falciparum malaria.
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 μM). 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 Ki of compound 67 is 0.10 μM). 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.
authors.affiliation: Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Videnović
authors.forename: Dejan M
authors.initials: DM
authors.lastname: Opsenica
authors.forename: James C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Laura
authors.initials: L
authors.lastname: Gomba
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Nuss
authors.forename: Zivota
authors.initials: Z
authors.lastname: Selaković
authors.forename: Jelena
authors.initials: J
authors.lastname: Konstantinović
authors.forename: Maja
authors.initials: M
authors.lastname: Krstić
authors.forename: Sandra
authors.initials: S
authors.lastname: Segan
authors.forename: Mario
authors.initials: M
authors.lastname: Zlatović
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sciotti
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Solaja
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors*; D002642:Chick Embryo; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D056945:Hep G2 Cells; D006801:Humans; D045726:Metalloproteases / Q000187:drug effects*; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D011480:Protease Inhibitors; D002738:Chloroquine; D045726:Metalloproteases; D019274:Botulinum Toxins, Type A
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