Hands-On Approach to Structure Activity Relationships: The Synthesis, Testing, and Hansch Analysis of a Series of Acetylcholineesterase Inhibitors

Abstract

This series of three practical sessions centers on drugs that inhibit the enzyme acetylcholineesterase. This enzyme is responsible for the inactivation of acetylcholine and has been the target of drugs to treat glaucoma and Alzheimer’s disease and for a number of insecticides and warfare agents. These sessions relate to a series of carbamate inhibitors that are classed as slowly reversible anticholinesterases and show how structure–activity relationships can guide the development of drug molecules. In Practical 1, each student group synthesizes one carbamate inhibitor of acetylcholinesterase. In Practical 2, students measure the activity of their inhibitor to derive an IC50 value suitable for comparison with the other derivatives made by the class. In Practical 3, students gain firsthand experience with structure–activity methods, such as a Hansch analysis, to investigate whether these can be used to make predictions of the activity of related compounds based on structural properties. This series gives students a rare insight into a number of the important aspects of drug discovery, that of drug synthesis, activity testing, and the construction of subsequent quantitative structure–activity relationships (QSARs).