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

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

On the mechanism of asymmetric allylation of aldehydes with allyltrichlorosi lanes catalyzed by QUINOX, a chiral lsoquinoline N-oxide

Allylation of aromatic alclehydes 1a-m with allyl- and crotyl-trichlorosilanes 2-4, catalyzed by the chiral N-oxide QUINOX (9), has been found to exhibit a significant dependence on the electronics of the aldehyde, with p-(trifluoromethyl)benzaldehyde 1g and its p-methoxy counterpart 1h affording the corresponding homoallylic alcohols 6g,h in 96 and 16% ee, respectively, at -40 degrees C. The kinetic and computational data indicate that the reaction is likely to proceed via an associative pathway involving neutral, octahedral silicon complex 22 with only one molecule of the catalyst involved in the rate- and selectivity-determining step. The crotylation with (E) and (Z)-crotyltrichlorosilanes 3 and 4 is highly diastereoselective, suggesting the chairlike transition state 5, which is supported by computational data. High-level quantum chemical calculations further suggest that attractive aromatic interactions between the catalyst 9 and the aldehyde 1 contribute to the enantiodifferentiation and that the dramatic drop in enantioselectivity, observed with the electron-rich aldehyde 1h, originates from narrowing the energy gap between the (R)- and (S)reaction channels in the associative mechanism (22). Overall, a good agreement between the theoretically predicted enantioselectivities for la and 1h and the experimental data allowed to understand the specific aspects of the reaction mechanism