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.

Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: A review

“…Recently, Idenovi et al [106] reported a new class of hybrid molecule (CQ-Cholic acid derivatives, 41a and b, Figure 31) which was originally intended to develop as Botulinum neurotoxin inhibitors [106][107][108], but further study indicated that they are better inhibitors of malarial parasite too [106]. The hybrid compounds showed better activity profile on some strains than the standard drugs CQ, artemisnin and MFQ.…”

Newly Designed Quinolinol Inhibitors Mitigate the Effects of Botulinum Neurotoxin A in Enzymatic, Cell-Based, and ex Vivo Assays

“…23–31 Zinc-chelating molecules have been shown to be privileged inhibitor scaffolds against zinc metalloproteases e.g. matrix metalloproteinases (MMPs); 32–34 for this reason, hydroxamates have been intensely studied as BoNT/A inhibitors.…”

Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice

“…IR (ATR): 3267w, 3060w, 3021w, 2917w, 2852w, 1609m, 1579s, 1531m, 1473w, 1449m, 1368w, 1329m, 1278w, 1241w, 1201w, 1167w, 1137w, 1118w, 1080w, 1040w, 876m, 800s cm À1 . 1 (18). 2-Formyl-5-(4 0 -methylphenyl)thiophene (100 mg, 0.49 mmol) and ACQ3 (173 mg, 0.74 mmol) were coupled to afford 18 (120.5 mg, 58%) using AcOH (42 lL, 0.74 mmol) and NaBH 4 (111 mg, 2.94 mmol).…”

“…strains. 15,16 Our own research in the field of antimalarial ACQs afforded adamantane- 17 and steroidal-derived compounds, 18 2 and 3, respectively, as well as simple aminoquinolines bound to a single aromatic ring 4a and 4b, 19 Figure 1.…”