Synthesis of tacrine analogues and their structure-activity relationships

Three man synthetic routes to analogues of tacrine are described: reaction of anthranilonitriles with cyclohexanone and other ketones, reaction of var ious anilines with alpha-cyanoketones, and reactions involving anilines and cyclic beta-ketoesters. Although tacrine has a wide range of pharmacologic al effects, it is best known as an inhibitor of cholinesterase enzymes. Man y of the analogues that have been made have not been tested against acetylc holinesterase or butyrylcholinesterase activity. Consequently, there is lim ited information from which a detailed understanding of structure-activity relationships can be derived. However, some halogenated derivatives are not only more potent acetylcholinesterase inhibitors than tacrine, they are al so more selective for acetylcholinesterase than for butyrylcholinesterase.