This work is dedicated to the memory of Prof. Paolo Sanna 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 1 H-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.
In the course of our work aimed at developing novel heterocycles of pharmaceutical interest, a new tricycle, the tetrahydropyrrolo[1,2-a]indole-1,8-dione, has been synthesized by an intramolecular Friedel-Crafts acylation, as a synthon suitable to be functionalized to give novel compounds with potential biological properties. Also, an unusual nucleophilic α-addition to methyl propiolate by 1,5,6,7-tetrahydro-4H-indol-4-one was observed and discussed.
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