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

Kundu Mrinalkanti (TCGLS Member); Dutta Aditi (TCGLS Member); Mal Sajal K (TCGLS Member); Karmakar Shouvik (TCGLS Member); Mandal Aritra (TCGLS Member); Mondal Susanta K (TCGLS Member); Kumar Sanjay (TCGLS Member); Saha Soumya (TCGLS Member); Pradhan Subhankar (TCGLS Member); Sarkar Ratul (TCGLS Member); Chakrabarti Monali (TCGLS Member); Malik Pradip K (TCGLS Member); Banerjee Manish (TCGLS Member); Roy Kuldeep K

Publication: Chemical biology & drug design, ASAP

DOI: 10.1111/cbdd.14170

Abstract: 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.