Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model

Satish N. Dighe; Eugenio De la Mora; Stephen Chan; Srinivas Kantham; Gawain McColl; Jared A. Miles; Suresh Kumar Veliyath; B. Yogi Sreenivas; Zeyad D. Nassar; Israel Silman; Joel L. Sussman; Martin Weik; Ross P. McGeary; Marie-Odile Parat; Xavier Brazzolotto; Benjamin P. Ross

doi:10.1038/s42004-019-0133-4

Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model

Satish N. Dighe, Eugenio De la Mora, Stephen Chan, Srinivas Kantham, Gawain McColl, Jared A. Miles, Suresh Kumar Veliyath, B. Yogi Sreenivas, Zeyad D. Nassar, Israel Silman, Joel L. Sussman, Martin Weik, Ross P. McGeary, Marie-Odile Parat, Xavier Brazzolotto, Benjamin P. Ross^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

Abstract

The development of polyphenols as drugs for Alzheimer's disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful development of stable, druglike polyphenolic analogues of the current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities and multifunctional properties for AD treatment. The compounds inhibit cholinesterases and amyloid beta (A beta) fibrillation, protect against A beta(42)-induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing A beta(42), with potencies similar to rivastigmine and natural polyphenols. The results suggest that a tertiary amine substituent is amenable for developing water-soluble, membrane-permeable polyphenols, and its incorporation adjacent to a hydroxy group is favourable for intramolecular hydrogen bonding that facilitates membrane permeability. Carbamylation of one hydroxy group protects the polyphenols from degradation and mostly improves their membrane permeability. These design strategies may assist in the development of polyphenol-based drugs.

Original language	English
Article number	35
Number of pages	14
Journal	Communications Chemistry
Volume	2
DOIs	https://doi.org/10.1038/s42004-019-0133-4
Publication status	Published - 22 Mar 2019

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Dighe, S. N., De la Mora, E., Chan, S., Kantham, S., McColl, G., Miles, J. A., Veliyath, S. K., Sreenivas, B. Y., Nassar, Z. D., Silman, I., Sussman, J. L., Weik, M., McGeary, R. P., Parat, M.-O., Brazzolotto, X., & Ross, B. P. (2019). Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model. Communications Chemistry, 2, Article 35. https://doi.org/10.1038/s42004-019-0133-4

@article{1ef18de047fc43798cb64fac090e73fe,

title = "Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model",

abstract = "The development of polyphenols as drugs for Alzheimer's disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful development of stable, druglike polyphenolic analogues of the current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities and multifunctional properties for AD treatment. The compounds inhibit cholinesterases and amyloid beta (A beta) fibrillation, protect against A beta(42)-induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing A beta(42), with potencies similar to rivastigmine and natural polyphenols. The results suggest that a tertiary amine substituent is amenable for developing water-soluble, membrane-permeable polyphenols, and its incorporation adjacent to a hydroxy group is favourable for intramolecular hydrogen bonding that facilitates membrane permeability. Carbamylation of one hydroxy group protects the polyphenols from degradation and mostly improves their membrane permeability. These design strategies may assist in the development of polyphenol-based drugs.",

author = "Dighe, {Satish N.} and {De la Mora}, Eugenio and Stephen Chan and Srinivas Kantham and Gawain McColl and Miles, {Jared A.} and Veliyath, {Suresh Kumar} and Sreenivas, {B. Yogi} and Nassar, {Zeyad D.} and Israel Silman and Sussman, {Joel L.} and Martin Weik and McGeary, {Ross P.} and Marie-Odile Parat and Xavier Brazzolotto and Ross, {Benjamin P.}",

year = "2019",

month = mar,

day = "22",

doi = "10.1038/s42004-019-0133-4",

language = "English",

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journal = "Communications Chemistry",

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publisher = "Nature Publishing Group",

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Dighe, SN, De la Mora, E, Chan, S, Kantham, S, McColl, G, Miles, JA, Veliyath, SK, Sreenivas, BY, Nassar, ZD, Silman, I , Sussman, JL, Weik, M, McGeary, RP, Parat, M-O, Brazzolotto, X & Ross, BP 2019, 'Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model', Communications Chemistry, vol. 2, 35. https://doi.org/10.1038/s42004-019-0133-4

TY - JOUR

T1 - Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model

AU - Dighe, Satish N.

AU - De la Mora, Eugenio

AU - Chan, Stephen

AU - Kantham, Srinivas

AU - McColl, Gawain

AU - Miles, Jared A.

AU - Veliyath, Suresh Kumar

AU - Sreenivas, B. Yogi

AU - Nassar, Zeyad D.

AU - Silman, Israel

AU - Sussman, Joel L.

AU - Weik, Martin

AU - McGeary, Ross P.

AU - Parat, Marie-Odile

AU - Brazzolotto, Xavier

AU - Ross, Benjamin P.

PY - 2019/3/22

Y1 - 2019/3/22

N2 - The development of polyphenols as drugs for Alzheimer's disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful development of stable, druglike polyphenolic analogues of the current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities and multifunctional properties for AD treatment. The compounds inhibit cholinesterases and amyloid beta (A beta) fibrillation, protect against A beta(42)-induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing A beta(42), with potencies similar to rivastigmine and natural polyphenols. The results suggest that a tertiary amine substituent is amenable for developing water-soluble, membrane-permeable polyphenols, and its incorporation adjacent to a hydroxy group is favourable for intramolecular hydrogen bonding that facilitates membrane permeability. Carbamylation of one hydroxy group protects the polyphenols from degradation and mostly improves their membrane permeability. These design strategies may assist in the development of polyphenol-based drugs.

AB - The development of polyphenols as drugs for Alzheimer's disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful development of stable, druglike polyphenolic analogues of the current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities and multifunctional properties for AD treatment. The compounds inhibit cholinesterases and amyloid beta (A beta) fibrillation, protect against A beta(42)-induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing A beta(42), with potencies similar to rivastigmine and natural polyphenols. The results suggest that a tertiary amine substituent is amenable for developing water-soluble, membrane-permeable polyphenols, and its incorporation adjacent to a hydroxy group is favourable for intramolecular hydrogen bonding that facilitates membrane permeability. Carbamylation of one hydroxy group protects the polyphenols from degradation and mostly improves their membrane permeability. These design strategies may assist in the development of polyphenol-based drugs.

U2 - 10.1038/s42004-019-0133-4

DO - 10.1038/s42004-019-0133-4

M3 - Article

SN - 2399-3669

VL - 2

JO - Communications Chemistry

JF - Communications Chemistry

M1 - 35

ER -

Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model

Abstract

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