Novel Sustainable-by-Design HDAC Inhibitors for the Treatment of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) represents a global problem, with an estimation of the majority of dementia patients in low- and middle-income countries by 2050. Thus, the development of sustainable drugs has attracted much attention in recent years. In light of this, taking inspiration from the HDAC inhibitor vorinostat (<b>1</b>), we develop the first HDAC inhibitors derived from cashew nut shell liquid (CNSL), an inexpensive agro-food waste material. CNSL derivatives <b>8</b> and <b>9</b> display a HDAC inhibitory profile similar to <b>1</b>, together with a more promising safety for <b>9</b> compared to <b>1</b>. Moreover, both compounds and particularly <b>9</b> were able to effectively modulate glial cell-induced inflammation and to revert the pro-inflammatory phenotype. All these results demonstrate that the use of inexpensive food waste materials could be successfully applied for the development of accessible and sustainable drug candidates for the treatment of AD.