Abstract
Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC(50) = 0.0042 μM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC(50) = 0.012 μM; hERG IC(50) = 0.63 μM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC(50) = 0.017 μM; gametocytes PfiGc/PfLGc IC(50) = 1.24/1.39 μM, and liver-stage PbHepG2 IC(50) = 2.30 μM), good microsomal metabolic stability (MLM CL(int) < 11 μL·min(-1)·mg(-1), E(H) < 0.33), and solubility (150 μM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg(-1) resulting from poor permeability (log D(7.4) = -0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.