The benzazole scaffold: a SWAT to combat Alzheimer's disease

Abstract

Neurodegenerative disorders including Alzheimer's disease (AD) are drawing scientists' attention within various fields, being one of the most serious diseases mankind will have to fight against in the very near future. AD is multi-factorial and is characterized by two histopathological hallmarks: the senile plaques made of amyloid-β (Aβ) peptide fibrils which also contain high levels of transition metal ions and the neurofibrillary tangles of Tau protein. Aβ aggregation, possibly modulated by metal ions, is now considered as an important factor in AD aetiology. Hence, chemists are studying the details of molecular features at the origin of the disease with special interest in Aβ aggregation and in the design of new molecules for the early diagnosis of AD or with curative properties. In this context, the benzazole molecular scaffold, included for instance in Thioflavin-T, an Aβ fibril specific dye, or the PIB imaging agent, appears to be very attractive and exhibits multiple uses. In the present review, we have thus focused our interest on the applications of benzazole derivatives for understanding, diagnosing and curing AD. After having analysed the synthetic access to 2-arylbenzazoles, we have described a selection of recent applications of such compounds aiming to combat AD. They include the use of Thioflavin-T for the monitoring of Aβ aggregation, the investigations of new PET and SPECT imaging agents for the detection of the senile plaques, the development of bi-functional molecules, encompassing the 2-arylbenzazole moiety for Aβ binding and a chelating unit for metal ions coordination for instance.

How Zn can impede Cu detoxification by chelating agents in Alzheimer's disease: a proof-of-concept study

“…8,23,53 Strategies to go further towards potential therapeutic applications include: (i) improving the BBB penetration ability, for instance by addition of sugar moieties, 11,39 or (ii) moving towards multi-functional ligands able to target specific aggregation states, for instance. 11,54 Lastly, it is worth mentioning that most if not all amyloid related pathologies (such as Parkinson, ALS, etc. ) also involved several metal ions (Fe, Cu and Zn) with various toxicities.…”

Tacrine-allyl/propargylcysteine–benzothiazole trihybrids as potential anti-Alzheimer's drug candidates

“…14,22 Furthermore this new set of eight hybrids was designed by selection of suitable linkers to enable a dual mode binding, via the tacrine and BTA moieties, with both active binding sites of AChE. Besides the description of the design and synthetic procedures, we include herein the results and discussion of the bioassays, namely the inhibition of AChE, Af3 aggregation, MAOs and anti-oxidant properties, as well as their effect on the neuronal cell viability upon being subjected to model stressors of AD.…”

CuII Binding to Various Forms of Amyloid‐β Peptides: Are They Friends or Foes?

“…[57,58] A very classic assay relies on the use of Thioflavin-T (ThT), a dye that shows a characteristic redshift in the excitation spectrum and strong enhancement of the fluorescence quantum yield upon binding to fibrillary structures. [59][60][61][62] Amyloid fibrils are characterized by laminated -sheets, the strands of which run perpendicular to the long axis of the fibril. [59,62,63] This amyloid composition produces the characteristic reflections (ca.…”

“…[59][60][61][62] Amyloid fibrils are characterized by laminated -sheets, the strands of which run perpendicular to the long axis of the fibril. [59,62,63] This amyloid composition produces the characteristic reflections (ca. 5 and 10 Å) observed in X-ray diffraction experiments, which are attributed to the strand spacing within and between -sheet layers, respectively.…”