New isoxazolidinyl-based N-alkylethanolamines as new activators of human brain carbonic anhydrases

Carbonic anhydrases (CAs) are widespread metalloenzymes which catalyse the reversible hydration of carbon dioxide (CO2) to bicarbonate (HCO3 (-)) and a proton, relevant in many physiological processes. In the last few years, the involvement of CA activation in different metabolic pathways in the human brain addressed the research to the discovery of novel CA activators. Here, a new series of isoxazoline-based amino alcohols as CA activators was investigated. The synthesis and the CA activating effects towards four human CA isoforms expressed in the human brain, that are hCAs I, II, IV and VII, were reported. The best results were obtained for the (methyl)-isoxazoline-amino alcohols 3 and 5 with K-A values in the submicromolar range (0.52-0.86 mu M) towards hCA VII, and a good selectivity over hCA I. Being hCA VII involved in brain function and metabolism, the newly identified CA activators might be promising hit compounds with potential therapeutic applications in ageing, epilepsy or neurodegeneration.

Automated summary

Carbonic anhydrases (CAs) are enzymes that catalyze the hydration of carbon dioxide, playing important roles in physiological processes. This study investigated a new series of isoxazoline-based amino alcohols as CA activators and found that compounds 3 and 5 showed the best activation effects towards hCA VII, with submicromolar affinity and good selectivity over hCA I. These newly identified CA activators have potential therapeutic applications in aging, epilepsy, and neurodegeneration.