Dual targeting of cholinesterase and amyloid beta with pyridinium/isoquinolium derivatives

Abstract

With the surge in the cases of Alzheimer's disease (AD) over the years, several targets have been explored to curb the disease. Cholinesterases, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), remain to be the available targets that are amendable to currently approved treatments. In this study, a series of novel compounds based on tramiprosate, a highly specific amyloid beta (Aβ) inhibitor, was designed to inhibit AChE, BuChE, and Aβ aggregation. In particular, the addition of a pyridinium/isoquinolinium ring to the tramiprosate moiety (to give compounds 3a–j) led to an increase in the binding affinity for the catalytic active site of cholinesterase, which was hampered by the presence of sulfonic acid. Exclusion of the sulfonic acid moiety led to a novel but effective class of cholinesterase inhibitors (9a–w). in vitro Aβ aggregation inhibition assay indicated that compounds 3a–j, 9e–f, 9i–l, 9q, 9r, 9u–w, and 12 could inhibit over 10% Aβ aggregation at 1 mM concentration. Cholinesterase inhibition assay suggested that compounds 9g, 9h, 9o, and 9q–t exhibit over 70% inhibition on both AChE and BuChE at a concentration of 100 μM. Amongst the designed molecules, compound 9r (ca 18% at 1 mM) showed comparable inhibitory effect on the inhibition of Aβ aggregation with tramiprosate (ca 20% at 1 mM), along with impressive cholinesterase inhibitory potential (AChE IC50 = 13 μM and BuChE IC50 = 12 μM), acceptable toxicity and ability to pass through blood brain barrier, which could be used to ameliorate the phenotypes of AD in preclinical models.

An Isoquinolinium Dual Inhibitor of Cholinesterases and Amyloid β Aggregation Mitigates Neuropathological Changes in a Triple-Transgenic Mouse Model of Alzheimer’s Disease

“…The multifactorial etiology of AD has led to research into MTDLs as an emerging strategy to tackle this disease. , ChE inhibition is regarded as the most common approach that is available for AD treatment for now. The amyloid hypothesis is one of the most prevailing theories for AD etiology and has attracted considerable attention in AD drug discovery. , Recently, we have reported some dual inhibitors of ChE activity and Aβ aggregation . We found that 9Q outperformed donepezil in the inhibition of BuChE.…”

“…Compound 9Q (Figure ) was synthesized as previously described . Donepezil and tramiprosate were purchased from Aladdin Co. (Shanghai, China).…”

“…The MALDI TOF MS (Microflex, Bruker) was used to determine the residual monomeric Aβ content in aggregating solutions. The detailed analytical method has been reported, and readers are directed to the literature for methodological details …”

“…Recently, the application of multitarget-directed ligands (MTDLs) has been reported as a very powerful and promising approach to tackle AD. , AChEI-based MTDLs were reported to modulate the disease by not only enhancing the acetylcholine action but also inhibiting Aβ aggregation and scavenging oxygen radicals. − In the present study, we carried out extensive pharmacological evaluation of a previously reported dual inhibitor of ChEs and Aβ aggregation, 9Q (see Figure ), using in vitro models and triple transgenic AD (3xTg-AD) mouse model. Cerebral accumulation of 9Q and the acetylcholine content in mouse brains were determined to evaluate, respectively, the blood–brain barrier (BBB) penetration ability of 9Q and the enhancement of acetylcholine in vivo .…”

Alzheimer's disease: A need for personalized therapeutic approaches

“…Different therapeutic approaches such as an inhibition of the degradation of acetylcholine (ACh) by inhibiting acetylcholine esterase (AChE) is currently used in patients to reduce disease symptoms without clear effect on disease progression (Wilkinson, Francis, Schwam, & Payne‐Parrish, 2004). Three papers in this issue report different approaches to develop a new AChE inhibitor (Carreiras et al 2020; Chakravarty, Ju, Chen, & Tam, 2019; Ciprés‐Flores et al, 2019). ACh can signal either through different nicotinic receptors or muscarinic receptors.…”