hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole

Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 mu M) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 mu M; hERG IC50 = 0.63 mu M), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 mu M; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 mu M, and liver-stage PbHepG2 IC50 = 2.30 mu M), good microsomal metabolic stability (MLM CLint < 11 mu L<middle dot>min(-1)<middle dot>mg(-1), E-H < 0.33), and solubility (150 mu M). It shows a similar to 6-fold and >6000-fold higher selectivity against human ether-a-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<middle dot>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.