Targeting cholinesterases with steroid hormone derivatives: Insights from In Vitro assays and molecular modeling

Steroids represent a large family of organic compounds that, as signaling molecules, play important role in variety of physiological processes as control of metabolic pathways, inflammation processes, immune response, and growth, development and reproduction. Modifying the steroid core has allowed the creation of novel synthetic derivatives, which can offer significant benefits in medicine for treating a wide range of pathological conditions. Quite a number of natural steroids have been identified as effective inhibitors of cholinesterases, pointing them out as potential therapeutic alternatives in the application in Alzheimer's disease (AD). Nevertheless, only a limited number of synthetic steroids have so far been studied as cholinesterase inhibitors, highlighting an opportunity for the development of new therapeutic agents derived from natural steroidal frameworks. In this study, we selected a set of structurally diverse steroid hormone derivatives and evaluated in vitro their inhibitory activity against human AChE and BChE. IC₅₀ values were estimated for several of the most active compounds, with pyridine-containing hydroxy derivative 8 exhibiting affinity toward BChE (IC₅₀ 2.76 µM), similar to that for clinically used cholinesterase inhibitors. In silico analyses suggest that hydrophobic interactions with key amino-acid residues predominantly govern the binding of these compounds within the enzyme's active site.