Wang-OSO 3 H catalyzed a greener approach for the synthesis of imidazo[1,2- a ]pyridin-3-amine derivatives as potential TNF-α inhibitors

The known anti-inflammatory activities of compounds containing the imidazo[1,2- a ]pyridin-3-amine prompted us exploring the TNF-α inhibitory properties of a series of compounds based on this framework. These compounds were accessed via an eco-friendly approach that involved Wang-OSO 3 H catalyzed 3-component reaction of 2-aminopyridines, aldehydes and isocyanides in aqueous media under ultrasound irradiation. This sonochemical method furnished a range of desired imidazo[1,2- a ]pyridin-3-amine derivatives in good to satisfactory yields. The intermediacy of an imine intermediate through which the reaction seemed to proceed has been demonstrated. In vitro evaluation of synthesized compounds against TNF-α led to the identification of compound 4a, 4b and 4d as initial hits with IC 50 in the range ∼6.2–6.9 µM. This was further supported by the in silico docking studies that revealed TYR135, TYR227, ILE231, LEU133 and LEU233 as the common interacting residues in the TNF-α trimer. Indeed, interaction with these residues is known to destabilize the TNF trimer that in turn could cause the intervention in its dynamics thereby weakening the interaction of TNF-α with the receptor for cellular signaling. Furthermore, compound 4a, 4b and 4d also showed good molecular alignment with the reference compound for interaction with TNF-α. The results of docking studies, in vitro assessment and in silico ADME predictions suggested further medicinal potential of the preliminary hits identified.