Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT4 receptors activities for the treatment of Alzheimer’s disease

Abstract

A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT4R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT4R.

Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity

“…In this ailment, there is an impairment of the cerebral cortex with complex processes; involving the production of senile plaques, neurofibrillary tangles, synapse loss and neuroinflammation; leading to the progressive cognitive decline and memory loss [ 2 , 3 ]. At the present time, about 50 millions of people worldwide suffer from the disease, which creates a heavy burden on the health care systems of many countries [ 4 , 5 , 6 ]. Therefore, discovery of novel drugs for AD is an urgent task.…”

Therapeutic modulators of the serotonin 5-HT4 receptor: a patent review (2014-present)

“…In this context, Suven Life Science, Pfizer and Dainippon Sumimoto Pharm were particularly active to extend the protection of known structures after modulation of the aromatic core, the linker between the basic amine and its substituents. The nature of the aromatic moiety is crucial in order to maintain a good affinity but also the optimal partial agonist profile needed for the therapeutic application of these ligands[64]. A limited number of aromatic cores (monocyclic or bicyclic) were explored, including aminochlorobenzamide, indole and indazole, benzimidazolone, benzofurane or quinolone or benzisoxazole.…”

Terphenyl-based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein−Protein Interaction

“…Rigidification of a scaffold is a well-known strategy that may result in higher specificity and potency of smallmolecule inhibitors (Assadieskandar et al, 2019;Hanson et al, 2007;Lalut et al, 2020;Wu et al, 2018). We have used this approach to modify the biphenyl fragment of anti-PD-L1 inhibitors by removal of the methoxy connector between the biaryl and phenyl rings.…”