Identification of 5‐(3‐(methylsulfonyl)phenyl)‐3‐(4‐(methylsulfonyl)phenyl)‐3H‐imidazo[4,5‐b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin‐based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold‐hopping approach combined with docking studies for putative‐binding interactions with Plasmodium falciparum phosphatidylinositol‐4‐kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5‐(3‐(methylsulfonyl)phenyl)‐3‐(4‐(methylsulfonyl)phenyl)‐3H‐imidazo[4,5‐b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME‐PK studies. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC50 = 29 nM) with meager in vitro intrinsic clearance, moderate plasma‐protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies. Despite significant research in the past decades, malaria remains to be public health problem and marked nearly half a million deaths in 2016. A new imidazopyridine‐based compound has been identified through scaffold‐hopping approach followed by its putative‐binding mode, synthesis and biological investigation. As a result, compound 1 is revealed as potent, non‐cytotoxic, metabolically stable, permeable and orally bioavailable antimalarial agent.