Structure Report for: 6EUL

Brazzolotto, X., de la Mora, E., Dighe, S.N., Ross, B.P.

Title: Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model.
Dighe SN, De la Mora E, Chan S, Kantham S, McColl G, Miles JA, Veliyath SK, Sreenivas BY, Nassar ZD and Ross BP <6 more 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 (- 6)
Ref: Communications chemistry, 2:35, 2019 : PubMed
Abstract


ESTHER: Dighe_2019_Commun.Chem_2_35
PubMedSearch: Dighe 2019 Commun.Chem 2 35
Gene_locus related to this paper: human-BCHE, torca-ACHE
Inhibitor(s) related to this paper: 6EUL-BY2

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.