Investigation of the role of linker moieties in bifunctional tacrine hybrids

Todd J. Eckroat, Keith D. Green, Rebecca A. Reed, Joshua J. Bornstein, Sylvie Garneau-Tsodikova

Research output: Contribution to journalArticle

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3614-3623
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number12
DOIs
StatePublished - Jun 15 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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