New compounds from heterocyclic amines scaffold with multitarget inhibitory activity on Aβ aggregation, AChE, and BACE1 in the Alzheimer disease

The preset neurodegenerations in Alzheimer disease (AD) are due to several mechanisms such as amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, neurofibrillary tangles, cholinergic dysfunction, among others. The aim of this work was to develop multitarget molecules for the treatment of AD. Therefore, a family of 64 molecules was designed based on ligand structure pharmacophores able to inhibit the activity of beta secretase (BACE1) and acetylcholinesterase (AChE) as well as to avoid amyloid beta (A beta(1-42)) oligomerization. The backbone of designed molecules consisted of a trisubstituted aromatic ring, one of the substituents was a heterocyclic amine (piperidine, morpholine, pyrrolidine or N-methyl pyrrolidine) separated from the aromatic system by three carbon atoms. The set of compounds was screened in silico employing molecular docking calculations and chemoinformatic analyses. Based on Gibbs free energy of binding, binding mode and in silico predicted toxicity results, three of the best candidates were selected, synthesized, and evaluated in vitro; F3S4-m, F2S4-m, and F2S4-p. All three compounds prevented A beta(1-42) aggregation (F3S4-m in 30.5%, F2S4-p in 42.1%, and F2S4-m in 60.9%). Additionally, inhibitory activity against AChE (ki 0.40 mu M and 0.19 mu M) and BACE1 (IC50 15.97 mu M and 8.38 mu M) was also observed for compounds F2S4-m and F3S4-m, respectively. Despite the BACE IC50 results demonstrated that all compounds are very less potent respect to peptidomimetic inhibitor (PI-IV IC50 3.20 nM), we can still say that F3S4-m is capable to inhibit AChE and BACE1.

Automated summary

The aim of this study was to develop multitarget molecules for the treatment of Alzheimer's disease. A family of 64 molecules was screened in silico and three candidates were selected for synthesis and in vitro evaluation. The compounds showed inhibitory activity against BACE1 and AChE and could prevent aggregation of Aβ(1-42).