A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver and gametocyte stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the seventeen derivatives showed IC50s < 0.1 µM against the chloroquine (CQ)-sensitive Plasmodium falciparum NF54 (PfNF54) strain while maintaining submicromolar potency against the multidrug resistant strain, PfK1, with most showing low likelihood of cross-resistance with CQ. Selected analogues (PfNF54- IC50 < 0.1 µM) were tested for cytotoxicity on CHO cells and found to be highly selective (selectivity index > 100). The first ever gametocytes screening of AST and its analogues revealed their moderate activity (IC50: 1 - 5 µM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with three-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-haematin formation by the AST derivatives and their antiplasmodium IC50s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery.
Supplement 1 : Additional details of the structures of all derivatives assessed.
Supplement 2 : Excel file with the compounds SMILES format