Discovery of a Potent and Selective Hetero‐Bivalent AChE Inhibitor via Bioisosteric Replacement

Scaffold hopping of known active compounds is becoming a successful strategy for the development of new molecular series. [1, 2] This strategy is based on the assumption that the same biological activity can be exerted by newly designed compounds that maintain some essential features of the template but are structurally different otherwise. [3] Playing a central role in modern medicinal chemistry, scaffold hopping is based on the concept of molecular similarity and thus involves the use of techniques such as shape matching, pharmacophore and similarity searching, fragment and bioisosteric replacement. [4] At present, many examples of successful scaffold hopping are known. A milestone in this field has been the identification of GABA-receptor antagonists based on the 1,4-benzodiazepine molecular scaffold. After its discovery in the Fifties, many attempts were undertaken to improve both pharmacokinetic and pharmacodynamic profiles of benzodiazepines initially by exploring various substituents and later by scaffold hopping to identify completely new core structures. Compounds with a novel scaffold different from that of benzodiazepines are Zopiclone, Zolpidem and Zaleplon. [5] Among other drugs dis