Dighe_2019_Commun.Chem_2_35

Reference

Title : Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model. - Dighe_2019_Commun.Chem_2_35
Author(s) : 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 MO , Brazzolotto X , Ross BP
Ref : Communications chemistry , 2 :35 , 2019
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 (Abeta) fibrillation, protect against Abeta42-induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing Abeta42, 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.

PubMedSearch : Dighe_2019_Commun.Chem_2_35
PubMedID:
Gene_locus related to this paper: human-BCHE , torca-ACHE

Related information

Inhibitor 6EUL-BY2
Gene_locus 6EUL-BY2    human-BCHE    torca-ACHE
Structure 6EUL-BY2    human-BCHE    torca-ACHE    6EZ2    6EYF    6EUE

Citations formats

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 MO, Brazzolotto X, Ross BP (2019)
Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model.
Communications chemistry 2 :35

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 MO, Brazzolotto X, Ross BP (2019)
Communications chemistry 2 :35