2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder

A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC50 3.88 ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.

Graphical abstractSynthesis and SAR studies of analogues of Pirodavir 2 involving replacement of the benzoate group with various benzo-azole rings led to the discovery of the 2-ethoxybenzoxazole capsid binder 13 as a highly active HRV inhibitor.Figure optionsDownload full-size imageDownload as PowerPoint slide