Hitting Two Birds With One Stone: Dual Modulation of Brain Carbonic Anhydrases and Histone Deacetylases Boosts Memory Consolidation

Cognitive impairments, characterized by deficits in one or more cognitive domains, are common in several pathological conditions but remain inadequately addressed by available pharmacological treatments. Given the complexity and multifaceted mechanisms underpinning these deficits, multi-targeted directed ligands are emerging as promising strategies for developing more effective therapies. In this study, we reported the design, synthesis as well as In Vitro and Ex Vivo assessment of prototypic molecular scaffolds that activate the carbonic anhydrase (CA; EC 4.2.1.1) and inhibit the histone deacetylase (HDAC; EC 3.5.1.98) metalloenzymes. By using the novel object recognition paradigm, we found that these compounds significantly enhanced memory consolidation at doses 10 times lower than single-target reference compounds. Taken together, these results suggest that the dual modulation of CA and HDAC activities by means of a single hybrid molecular entity represents an innovative approach for the management of cognitive symptoms associated with neurodegenerative, neurodevelopment, and psychiatric disorders.