Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer’s disease

Abstract

Beside acetylcholinesterase, butyrylcholinestersase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT6 receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC50 = 0.97 µM). The latter will deliver after hydrolysis compound 6, a potent 5-HT6 receptors antagonist (Ki = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory.

Chemical Profiling and Biological Evaluation of Nepeta baytopii Extracts and Essential Oil: An Endemic Plant from Turkey

“…The inhibition of BChE has been advocated in the later stage of Alzheimer's disease. During the progression of the disease, the BChE level increases, exacerbating the conditions of the patient [43]. Herein, the ability of N. baytopii aerial parts extracts and essential oil to inhibit α-amylase and α-glucosidase was also evaluated.…”

UHPLC-MS Characterization and Biological Insights of Different Solvent Extracts of Two Achillea Species (A. aleppica and A. santolinoides) from Turkey

“…The inhibition of BuChE has been advocated in the later stage of Alzheimer’s disease. During the progression of the disease, BuChE level increases, exacerbating the conditions of the patient [ 56 ]. The ability of the extracts to inhibit enzymes targeted in the management of diabetes type II, namely α-amylase and α-glucosidase, was presented in Table 4 .…”

Approaches of Prodrug Designing to Treat Cancer, Neurodegenerative Disorders and Viral Diseases

“…Many Alzheimer disease drugs were being suggested but the major drawback is that all the drug targets one pathway (Oliveri, 2015) (Toublet et al, 2020) but ROS responsive prodrug is a multi-targeted directed ligand which shows anti-inflammatory activity and also inhibits the acetylcholinesterase enzyme. The ROS responsive prodrug therapy is the most advanced treatment for neurodegenerative disorder (Oliveri, 2015).…”

“…All the patients having neurodegenerative disorder are treated with acetylcholinesterase inhibitor but recent studies have shown that butyl cholinesterase is also responsible for the disease, so MTDL drug class named Pleiotropic prodrug was designed which targets more than one pathway (Toublet et al, 2020) (Christophe & Patrick, 2018). These are butyl cholinesterase inhibitor as well as 5HT6 receptor antagonist and the prodrug is pleiotropic carbamate (Toublet et al, 2020). Another novel drug name Revastigmine, a pleiotropic prodrug that inhibits acetylcholinesterase as well as also targets 5HT receptor mainly 5HT4 receptor.…”