Discovery of a novel highly potent broad-spectrum heterocyclic chemical series of arenavirus cell entry inhibitors

We identified and explored the structure?activity relationship (SAR) of a novel heterocyclic chemical series of arenavirus cell entry inhibitors. Optimized lead compounds, including diphenyl-substituted imidazo[1,2-a]pyridines, benzimidazoles, and benzotriazoles exhibited low to sub-nanomolar potency against both pseudotyped and infectious Old and New World arenaviruses, attractive metabolic stability in human and most nonhuman liver microsomes as well as a lack of hERG K + channel or CYP enzyme inhibition. Moreover, the straightforward synthesis of several lead compounds (e.g., the simple high yield 3-step synthesis of imidazo[1,2-a]pyridine 37) could provide a cost-effective broad-spectrum arenavirus therapeutic that may help to minimize the costprohibitive burdens associated with treatments for emerging viruses in economically challenged geographical settings.

Automated summary

The study identified a novel heterocyclic chemical series with potent activity against both Old and New World arenaviruses, showing attractive metabolic stability and lack of hERG K+ channel or CYP enzyme inhibition. Optimized lead compounds could provide a cost-effective broad-spectrum arenavirus therapeutic to help minimize treatment costs for emerging viruses in economically challenged geographical settings.