Polypharmacology-based strategies in Alzheimer's disease: the Yin and the Yan of Acetylcholinesterase inhibition

Drug discovery and development is a complex and expensive process. Due to the exponential growth of molecular data and fast advancement in technologies, the efforts of drug discovery have been tremendously amplified. The philosophy of drug design has been transformed from "one drug one target" to "one drug multiple targets", coined as polypharmacology . Polypharmacology is emerging as the next paradigm of drug discovery. Polypharmacological phenomena includes: (i) single drug acting on multiple targets of a unique disease pathway, or (ii) single drug acting on multiple targets pertaining to multiple disease pathways. In addition, polypharmacology for complex diseases, like Alzheimer's disease, is likely to employ multiple drugs acting on distinct targets, that are part of a networks regulating various physiological responses. The approach needs the systematic integration of the data derived from different disciplines including computational modeling, X-ray crystallography, synthetic chemistry, in vitro/in vivo pharmacological testing, and clinical studies. We report on the structure-activity relationships of novel multi-target direct ligands for the potential treatment of Alzheimer's disease, designed by combining a tacrine fragment to distinct pharmacophores with a linker of a suitable length. The compounds displayed excellent acetylcholinesterase inhibitory potencies and interesting capabilities to block beta-amyloid aggregation .