Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Abstract

Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.

Development of potent reversible selective inhibitors of butyrylcholinesterase as fluorescent probes

“…The binding mode of inhibitor 3 is somewhat different compared to that of inhibitors 1 and 2 [15][16][17] . The common property of all of these three types of inhibitors is the position of the naphthalene Figure 1.…”

“…The naphthalene-sulphonamide derivatives 3A and 3B have similar binding modes, where the naphthalene moiety points towards the acyl-binding pocket (Figures 4(B), 5(B)). The piperidine moiety is inverted compared to the naphthalene carboxamide of 2C (5NN0), although it retains the same orientation as in the parent sulphonamide (5DYW) 16 (Figure 5(B)), where the benzyl ring protrudes into a highly hydrophobic pocket that is formed by residues Phe73, Trp82, Tyr332, Trp430, and Tyr440. As seen for the complex structure of parent inhibitor 3 with BChE, the sulphonamide oxygens of 3A and 3B form H-bonds with the hydroxyl group of Thr120.…”

“…Inhibition of BChE in rat brain slices was therefore examined for probes 2C and 3B, to evaluate these two probes under more biologically relevant conditions. Sections of rat brain with the highest BChE activity were selected and the modified Koelle À Karnovsky histochemical method was used to detect BChE activity 16,[40][41][42] . For these probes 2C and 3B, 1 mM was needed to achieve substantial inhibition of BChE, as measured by less formation of the dark-brown/black granular BChE reaction product (Figure 8).…”

“…In the present study, we report on the two BChE-specific fluorescent probes that were derived from previously described highly potent and reversible BChE-selective inhibitors [15][16][17] . Although the incorporation of the fluorophore moieties had a negative impact on their BChE inhibition potency, the best three of these fluorescent inhibitors retained excellent activities in the low nanomolar range: probes 2A, 3A, and 3B.…”

Novel Sulfonamide-Based Analogs of Metformin Exert Promising Anti-Coagulant Effects without Compromising Glucose-Lowering Activity

“…However, the sulfonamide moiety has also been incorporated to known biologically relevant backbones to generate novel biological activity [ 3 ]. For instance, new anti-AD (Alzheimer’s disease) agents with inhibitory properties towards butyrylcholinestarase (BChE) have been synthesized by incorporation of sulfonamide moiety to earlier hit compounds [ 14 ]. These results suggest that sulfonamide-based compounds exert multi-directional biological activity.…”