DISCOVERY OF A NOVEL TETRAHYDROACRIDINE ACETYLCHOLINESTERASE INHIBITOR THROUGH AN INDEXED COMBINATORIAL LIBRARY

Background: Methods for the rapid and efficient preparation of drug ca ndidates through combinatorial chemistry are of increasing interest. W e have previously reported an indexed combinatorial library method tha t allows both the preparation and testing of compounds in solution. We set out to apply this method to develop more effective analogs of the known, marketed drug tacrine, an acetylcholinesterase inhibitor. Resu lts: A one-step condensation of cyclohexanones with cyanoanilines to g enerate tetrahydroacridine pools was developed. The resulting library of (formally) 72 tetrahydroacridines was screened against acetylcholin esterase, and a compound 10-fold more potent than tacrine, 7-nitrotacr ine, was discovered. Its increased potency could be readily explained by examining the known structure of the complex of acetylcholinesteras e with tetrahydroacridine. Conclusions: In this work, we have provided a relatively rare example of carbon-carbon bond formation in a pool s ynthesis, and have discovered a potentially useful acetylcholinesteras e inhibitor.