RESUMO
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 EC(50) 3.88ng/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.
Assuntos
Benzoatos/química , Benzoxazóis/química , Proteínas do Capsídeo/metabolismo , Rhinovirus/metabolismo , Benzoatos/metabolismo , Benzoxazóis/metabolismo , Humanos , Ligação Proteica/fisiologia , EstereoisomerismoRESUMO
A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
