N-Benzyl Benzamide Derivatives as Selective Sub-Nanomolar Butyrylcholinesterase Inhibitors for Possible Treatment in Advanced Alzheimer’s Disease

Abstract

Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel N-benzyl benzamide scaffold, inhibited BChE with IC 50 from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar K D value, which revealed that the compounds exert the inhibitory effect through directly binding to BChE. Several compounds showed neuroprotective effects verified by the oxidative damage model. Furthermore, the safety of S11-1014 and S11-1033 was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg S11-1014 or S11-1033 exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Aβ 1−42 . The pharmacokinetics studies characterized the metabolic stability of S11-1014. Thus, N-benzyl benzamide inhibitors are promising compounds with drug-like properties for improving cognitive dysfunction, providing a potential strategy for the treatment of Alzheimer's disease.

Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer’s Disease Mouse Model

“…Different to AChE, levels of butyrylcholinesterase (BChE) seem to increase during disease progression, marking it as a promising target for mid- and late-stage treatment of AD . Several studies by us and others could already underline beneficial effects of BChE inhibition in vivo regarding neuroprotective properties. ,,,,− …”

Design, Synthesis, and Proof of Concept of Balanced Dual Inhibitors of Butyrylcholinesterase (BChE) and Histone Deacetylase 6 (HDAC6) for the Treatment of Alzheimer’s Disease

“…In the past 5 years, a number of potent and selective BChE inhibitors have been developed through virtual screening and a series of structural optimizations (Figure ), such as S11-1014 ( 4 ), S08-3009 ( 5 ), and S06-1011 ( 6 ). − Among all these compounds, S11-1014 shows highly potent and selective inhibitory activity against BChE ( eq BChE IC 50 = 0.15 ± 0.06 nM, h BChE IC 50 = 0.08 ± 0.03 nM, h BChE K D = 3.18 nM, eq BChE, and h BChE are butyrylcholinesterase from equine and human serum, respectively). At the same time, this compound possesses reasonable physicochemical properties and relatively suitable BBB permeability.…”

“…In our previous research, we found that selective BChE inhibitors can protect against neuronal damage . Therefore, we next assessed the cytoprotective effect of the compounds against glutamate- and hydrogen peroxide-induced cell damage using the MTT assay (glutamate and hydrogen peroxide were carried out on SH-SY5Y and PC12 cells, respectively).…”

“…Because the structures of these two compounds have undergone a large change compared with the parent compound (S11-1014), the BChE inhibitory activities were significantly decreased, which is consistent with our previous studies. 41 The most potent compound was 23e (IC 50 = 0.4 ± 0.3 nM) with o-phenylenediamine and substitution at the meta-position of the A-ring with the 3-carbon linker. Overall, although the inhibitory activity of all dual inhibitors on BChE remained at a decent level, they were reduced to varying degrees relative to the parent compound S11-1014.…”

“…After replacing the benzene ring with an amino group, the activity will decrease by about 10-fold compared to S11-1014, which has been reported in our previous research. 41,42 Then, we tested the inhibition rates (IR) of all dual-target compounds against HDAC6 at 1.0 and 0.1 μM to preliminarily investigate the HDAC6 inhibition activity of the compounds; SAHA and TubA were chosen as the positive control. As shown in Tables 1 and 2, compounds with o-phenylenediamine seemed to have little inhibitory activity against HDAC6 (23a−l and 32) at both concentrations of 1.0 and 0.1 μM with IR values less than 10% (except 23a at 1.0 μM, IR = 13%).…”