TY - JOUR
T1 - Investigation of the role of linker moieties in bifunctional tacrine hybrids
AU - Eckroat, Todd J.
AU - Green, Keith D.
AU - Reed, Rebecca A.
AU - Bornstein, Joshua J.
AU - Garneau-Tsodikova, Sylvie
N1 - 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.
PY - 2013/6/15
Y1 - 2013/6/15
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bmc.2013.02.047
DO - 10.1016/j.bmc.2013.02.047
M3 - Article
C2 - 23535563
AN - SCOPUS:84878230024
SN - 0968-0896
VL - 21
SP - 3614
EP - 3623
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 12
ER -