A New Series of Amino Alcohol Oxime Ethers as Activators of Human Brain Carbonic Anhydrases: Advances in Selective Activation of Human Carbonic Anhydrase VII

Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyze the interconversion of carbon dioxide and water to bicarbonate and proton. Given CA crucial role in carbon-based life, CA inhibition is a well-known therapeutic strategy for several diseases. However, in recent years, CA activation has emerged as a promising therapeutic approach for neurodegenerative conditions such as Alzheimer's disease, generalized anxiety, phobias and post-traumatic stress disorder. In this study, a new series of amino alcohol oxime ethers was synthesized from hit compound A to enhance its activity and selectivity towards four brain hCA isoforms, particularly hCA VII, which plays a key role in regulating neuronal pH related to synaptic plasticity and cognitive performance. Herein, we report a structure–activity relationship analysis to identify compounds that are both potent and selective activators for hCA VII. Among the synthesized derivatives, the morpholino propyl compound 12 emerged as the most active (KA = 72 nM) and selective over other brain isoforms. These results were further supported by in silico studies, which revealed favorable binding interactions at site A due to structural features present in both R and S enantiomers of compound 12.