AN EVALUATION OF THE ANTIRHINOVIRAL ACTIVITY OF ACYLFURAN REPLACEMENTS FOR 3-METHYLISOXAZOLES - ARE 2-ACETYLFURANS BIOISOSTERES FOR 3-METHYLISOXAZOLES

As a probe of the 3-methylisoxazole portion of our broad-spectrum antipicornaviral series, a panel of 2-acetylfuran analogues was prepared as replacements for the 3-methylisoxazole ring. Comparison of the two series showed remarkable similarity in potency, spectrum of activity, log P, and electrostatic parameters. X-ray studies of 21b bound to human rhinovirus-14 showed that the 2-acetyl group adopted st syn conformation and the carbonyl oxygen acts as a hydrogen bond acceptor with ASN(219) in, much the same way as the nitrogen of the isoxazole. The importance of the syn conformation and the hydrogen-bonding capability was confirmed by the reduced antiviral activity of the 2-methylfuran and 2-formylfuran analogues. From the results of this study, it is apparent that the syn-2-acetylfuran ring is acting as a bioisostere for the 3-methylisoxazole.