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 IC 50 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).

Mapping research on biochemistry education: A bibliometric analysis

“…Two articles of this period reveal some positive aspects of the hands-on approach. In the first one, 54 the authors present three practical experimental activities to offer student groups an insight into several important aspects of drug discovery, such as drug synthesis, activity testing, and the construction of subsequent quantitative structure-activity relationships. The educational goal of the experiments was to expose students to the full spectrum of activities relevant to drug development and the achievement of this goal, as evidenced by the keen student performance in the practical report and the final exam.…”

Drug Synthesis and Analysis of an Acetylcholinesterase Inhibitor: A Comprehensive Medicinal Chemistry Experience for Undergraduates

“…22 Hexane is flammable and toxic (neurotoxin). 7 CHCl 3 and CDCl 3 have an anesthetic effect, and they are all potential carcinogens. 8 Acetyl chloride is irritating to the upper respiratory tract and causes coughing and chest pain after inhalation.…”

“…Comprehensive experiences have been shown to be highly influencing educational exercises that carry many benefits, such as improved scientific thinking and oral expression. , Besides the necessary chemical synthesis experiment curriculum, , many cross-cutting experimental curricula involving biological and computational parts were reported. − However, to our knowledge, a comprehensive experiment, involving the synthesis, bioactivity evaluation, computer simulation docking, and student-presentation, has yet to be implemented in the laboratory curriculum. Herein, a 4 week research-based experiment was designed and practiced for undergraduates.…”

“…In this experience, tacrine (9-amino-1,2,3,4-tetrahydroacridine), which was the first drug approved by the US FDA for the treatment of mild to moderate AD in 1993, was selected as the candidates, because its synthesis route was approachable for undergraduate students. Moreover, there are well-established assays and commercial kits to test the binding affinity of chemicals with AChE as it is a well-studied enzyme. On the other hand, abundant crystal structure sources of AChE were available on the PDB website (), , which were essential for the molecule docking experiment.…”

Drug Design – An experiment for chemistry class during preparation for the A‐levels

“…Es wurden mehrere Anläufe unternommen, es für den schulischen Einsatz zu erschließen , was ebenfalls seine Zukunftsrelevanz und Aktualität mit Blick auf die Chemiedidaktik unterstreicht. Auch zum Einsatz in der Hochschullehre wurden mehrere Publikationen zur Thematik veröffentlicht . Unter den Vorschlägen für den schulischen Kontext befinden sich beispielsweise Publikationen zur Synthese von Schmerzmitteln (Aspirin) und zum Austausch eines Substituenten zur besseren Wachstumshemmung von Bakterien ; auch wurden durch den Fonds der Chemischen Industrie Unterrichtsmaterialien, u. a. zu den Themen Verteilungskoeffizient Octanol/Wasser ( Lipinski rule of five ) und Antibiotika , publiziert.…”