Design, synthesis and biological evaluation of new H2S-releasing rivastigmine derivatives as neuroprotective molecules

Alzheimer's disease (AD) represents one of the main challenges for the 21st century medical research as no disease-modifying agent has been successfully progressed to the market, while the number of people affected by AD is estimated to grow exponentially over the next years. The complex network of triggering factors involved in the insurgence and progression of AD can be rightly addressed as one of the main reasons behind the difficulty in identifying new pharmacological approaches. For this reason, the discovery and development of drugs endowed with pleiotropic activity remain the most valuable, but at the same time challenging, approaches to tackle down AD. Interestingly, the combination of active pharmacophores through molecular hybridization - or Multi-Target Directed Ligand strategy (MTDL) - has not been explored enough for this disease, despite proving to be a successfully strategy in other field, such as oncology. To contribute to the development of new strategies against AD, we decided to explore the hybridization of the marketed drug rivastigmine - prescribed to ameliorate AD symptomatology - with moieties capable to release hydrogen sulfide (H₂S), a gasotransmitter with a key role in the neurological physiology of ageing. In particular, we identified compound 1, as a potent small molecule capable of inhibit AChE, preventing inflammation and ROS production in cultured neurons and microglia, triggering autophagy response and blocking Aβ fibrils propagation. Interestingly, the beneficial effects observed in vitro have been confirmed in vivo, since the rivastigmine derivative 1 improved the lifespan in a Caenorhabditis elegans model of AD.