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

Abstract

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.