title: Investigation of the role of linker moieties in bifunctional tacrine hybrids.
abstract: Alzheimer's disease (AD) is a complex neurological disorder with multiple inter-connected factors playing roles in the onset and progression of the disease. One strategy currently being explored for the development of new therapeutics for AD involves linking tacrine, a known acetylcholinesterase (AChE) inhibitor, to another drug to create bifunctional hybrids. The role and influence on activity of the linker moiety in these hybrids remains ill-defined. In this study, three series of 6-chlorotacrine with linkers varying in terminal functional group and length were synthesized, evaluated for AChE inhibition, and compared to tacrine and 6-chlorotacrine-mefenamic acid hybrids. Out of the compounds with terminal amine, methyl, and hydroxyl moieties tested, several highly potent molecules (low nanomolar IC50 values) comprised of linkers with terminal amines were identified. These 6-chlorotacrine with linkers were significantly more potent than tacrine alone and were often more potent than similar 6-chlorotacrine-mefenamic acid hybrids.
authors.affiliation: Department of Medicinal Chemistry in the College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-2216, USA.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Eckroat
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Reed
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Bornstein
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
mesh_terms: D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D013619:Tacrine; D002802:Cholinesterases