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 journalArticlepeer-review

16 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
Pages (from-to)3614-3623
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number12
DOIs
StatePublished - Jun 15 2013

Bibliographical note

Funding Information:
This work was supported by the Life Sciences Institute and the College of Pharmacy at the University of Michigan (S.G.-T.). The Alzheimer’s Art Quilt Initiative (AAQI) is also acknowledged for their support (S.G.-T.). T.J.E. is supported in part by endowment funds from Dr. Chingiu Wang Sheu in the College of Pharmacy at the University of Michigan. We thank Athena Flecha for help in the preparation of synthetic starting materials and compounds 9a and 9b . We thank Christopher K. Jones for help with modeling experiments.

Keywords

  • Acetylcholinesterase
  • Alzheimer's disease
  • Bifunctional molecules
  • Mefenamic acid
  • Tacrine

ASJC Scopus subject areas

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

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