Exploring dual inhibitors Carbonic Anhydrases and Phosphodiesterase 5 as potential agents for treatment Alzheimer's disease.

In this study, we report for the first time the design and evaluation of a series of compounds with potential therapeutic relevance for Alzheimer's disease (AD), able to inhibit both human Carbonic Anhydrase (hCA) isoforms most involved in this disease as well as Phosphodiesterase 5 (PDE5), using sildenafil as the structural scaffold. A total of 19 new dual-target molecules were synthesized and biologically assessed, leading to the identification of compound 8a as the most promising candidate, exhibiting potent inhibition toward both enzymatic targets. The binding interactions of three selected derivatives (6, 8a, and 10d) with hCA II were elucidated by X-ray crystallography experiments. Moreover, compound 8a demonstrated a favourable safety profile, as it did not markedly impair cell viability on differentiated SH-SY5Y at concentrations up to 100 μM and conferred protection against Aβ-induced cytotoxicity showing superior efficacy compared to the single-target reference agents acetazolamide (AAZ) and sildenafil in mitigating oxidative stress. In vivo, chronic administration of compound 8a prevented deficits in both recognition and working memory in Aβ1-42-infused mice, outperforming vehicle-treated controls. Collectively, these findings highlight the potential of dual CA/PDE5 inhibition as a novel therapeutic strategy for Alzheimer's disease.