Novel Isoindole-1,3-Dione-Isoxazole Hybrids: Synthesis, Characterization, Evaluation of Their Inhibitory Activities on Carbonic Anhydrase and Acetylcholinesterase.

It is known that compounds containing isoxazole units exhibit a high potential for biological activity due to the isoxazole ring. In this study, eight hexahydro-5H-isoxazolo[4,5-f]isoindole-5,7(6H)-dione derivatives bearing isoxazole moieties were synthesized and their inhibitory effects on various metabolic enzymes, including acetylcholinesterase (AChE) and human carbonic anhydrase isoforms I and II (hCA I and hCA II), which are associated with global disorders such as Alzheimer's disease (AD), epilepsy, and glaucoma, were investigated. Among the synthesized compounds, derivatives 9-12 exhibited notable inhibitory activity against AChE, hCA I, and hCA II enzymes. The IC50 values were determined to be in the ranges of 4.65-12.83 nM for AChE, 23.17-79.58 nM for hCA I, and 36.58-88.28 nM for hCA II. Molecular docking studies of the synthesized compounds 9a-12a were carried out against three proteins: 1AZM (Human carbonic anhydrase I), 5AML (three-dimensional structure of human carbonic anhydrase II) and 4EY6 (recombinant human acetylcholinesterase). AZA and Tacrine were used as references in the docking analyses. All compounds were determined to have a higher binding affinity than Tacrine (-7.04 kcal/mol) and AZA (-6.12 and -6.24 kcal/mol). The results of inhibition tests showed that some isoxazole derivatives (9-12) showed significant inhibitory effects against both CA and AChE enzymes.