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

PMCID: PMC12174897

PMID: 40528640

DOI: 10.1002/ardp.70020

Journal: Archiv der Pharmazie

Publication Date: 2025-6-18

Authors: Costa A, Bozdag M, Renzi G, Rani B, Passani MB, et al.

Key Points

• Multi-targeted molecular approach shows promise for cognitive impairment treatment
• Compounds 12 and 14 demonstrated memory enhancement at doses 10x lower than single-target treatments
• Dual CA activation and HDAC inhibition represents an innovative neurotherapeutic strategy

Summary

This research explores an innovative multi-targeted therapeutic approach for addressing cognitive impairments by developing dual-action molecular compounds that simultaneously activate carbonic anhydrase (CA) and inhibit histone deacetylase (HDAC). The study designed and synthesized novel hybrid molecules (compounds 12 and 14) that demonstrate enhanced memory consolidation at significantly lower doses compared to single-target treatments, suggesting a promising strategy for managing cognitive symptoms across neurodegenerative, neurodevelopmental, and psychiatric disorders.

Using the novel object recognition paradigm, researchers found that compounds 12 and 14 significantly improved memory performance, with statistically significant discrimination index values (p < 0.01) at a 5 nmol/µL dose. These compounds exhibited broad CA isoform activation across multiple human enzyme variants, with particularly notable activity in CA I, II, and VII, while maintaining low toxicity and high specificity compared to reference compounds.