Novel Pyrazinoindolones As Amyloid‐Beta Aggregation Inhibitors

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a devastating neurodegenerative condition which primarily affects the elderly population. One of hallmarks of AD is the accumulation of protein aggregates known as amyloid‐beta (Aβ) that promotes neurotoxicity and cognitive decline. Recent discoveries in the field led to the accelerated market approval of anti‐Aβ antibodies aducanumab and lecanemab. These are exciting discoveries. However, considering the cost and patient compliance issues with these biological therapies, discovering novel anti‐Aβ therapies that are based on small molecules is highly desirable due to several advantages over biological therapies including the ease of oral administration, reduced cost involved in bulk manufacturing and better stability on storage.MethodA library of novel pyrazino[1,2‐a]indole‐1(2H)‐one derivatives were designed using the computational modeling software Discovery Studio Structure‐Based‐Design (Biovia Inc, San Diego USA). Then synthetic chemistry protocols were optimized to prepare small molecule library and were characterized by 1H and 13C NMR and Liquid Chromatography Mass Spectrometry studies. The anti‐Aβ activity of these novel molecules toward Aβ40 aggregation was evaluated by fluorescence spectroscopy using the thioflavin‐T based aggregation kinetic studies. In addition, the online web tool SwissADME was used to calculate the physicochemical properties of pyrazino[1,2‐a]indole‐1(2H)‐one derivatives to assess their drug‐likeness, blood‐brain barrier permeability and pharmacokinetics.ResultA novel library of pyrazino[1,2‐a]indole‐1(2H)‐one derivatives were prepared by optimizing a four step or two step synthesis protocol starting from either phenylhydrazine or indole‐2‐carboxylic acid to afford pyrazino[1,2‐a]indole‐1(2H)‐one derivatives 5a–f. In the Aβ40 (5 μM) aggregation kinetics assay, they exhibited 14‐59% inhibition when tested at a range of concentrations (1, 5, 10 and 25 μM), demonstrating their anti‐Aβ properties. Their physicochemical properties suggest their drug‐likeness.ConclusionStructure‐activity relationship studies demonstrate that the fused tricyclic pyrazino[1,2‐a]indole‐1(2H)‐one is a suitable template to i) develop novel chemical tools to study and understand the mechanisms of Aβ40 aggregation and ii) discover novel small molecules as potential therapies for AD.