Structural Investigation of 3,5-Disubstituted Isoxazoles by1H-Nuclear Magnetic Resonance

HIV-1 integrase (IN) is a very promising and validated target for the development of therapeutic agents against AIDS. In an effort to design and synthesize biological isosteric analogs of β-diketoacid-containing inhibitors of IN, we prepared a series of substituted isoxazole carboxylic acids. Several of these compounds inhibited catalytic activities of purified IN at micromolar concentration range. With an aim to prepare a large number of analogues based on the isoxazole pharmacophore we focused our study on a series of 3,5-disubstituted isoxazole isomers. For a rapid structural analysis we discovered a convenient 1H-nmr method for distinguishing between isomeric structures based on their H-4 assignments. This "finger print" approach to isomer identification will be useful in combinatorial chemistry settings where a mixture can be further derivatized.