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. 2023 Dec 22;29(1):72.
doi: 10.3390/molecules29010072.

Rivastigmine-Bambuterol Hybrids as Selective Butyrylcholinesterase Inhibitors

Jie Wu  1 , Zekai Tan  2 , Marco Pistolozzi  3 , Wen Tan  4   5   6
Affiliations

Rivastigmine-Bambuterol Hybrids as Selective Butyrylcholinesterase Inhibitors

Jie Wu et al. Molecules. .

Abstract

Selective butyrylcholinesterase inhibitors are considered promising drug candidates for the treatment of Alzheimer's disease. In this work, one rivastigmine-bambuterol hybrid (MTR-1) and fourteen of its analogues were synthesized, purified, and characterized. In vitro cholinesterase assays showed that all the compounds were more potent inhibitors of BChE when compared to AChE. Further investigations indicated that MTR-3 (IC50(AChE) > 100,000 nM, IC50(BChE) = 78 nM) was the best compound in the series, showing high butyrylcholinesterase selectivity and inhibition potency, the potential to permeate the blood-brain barrier, and longer-lasting BChE inhibition than bambuterol. These compounds could be used to discover novel specific BChE inhibitors for the treatment of Alzheimer's disease.

Keywords: Alzheimer’s disease; bambuterol; butyrylcholinesterase; hybrid; rivastigmine.

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Conflict of interest statement

Author Wen Tan was employed by the company Post-Doctoral Innovation Site, Jinan University Affiliation, Yuanzhi Health-Tech Inc. and Kesi (Shandong) Innovation Service Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Structures of bambuterol, rivastigmine and MTR-1. * chiral center.
Scheme 1
Scheme 1
Synthesis of compounds. (a) Ethyl acetate, K2CO3•3/2H2O, K2CO3, pyridine, 70 °C; (b) ethyl acetate:CHCl3 = 1:1, CuBr2, 60 °C; (c) methanol, NaBH4, CH2Cl2; (d) isopropanol, 80 °C; (e) HCl in ethanol, 0 °C. * chiral center.
Figure 2
Figure 2
Time- and concentration-dependent inhibition of eqBChE (A) after pre-incubation with various concentrations of MTR-3. Linear correlation of the kobs values obtained for MTR-3 versus its respective concentrations ((B) eqBChE).
Figure 3
Figure 3
(A) Activity recovery of eqBChE after inhibition with MTR-3. (B) Decarbamylation kinetics of carbamylated eqBChE determined using Equation (4). Data are represented in the form of mean ± SD values (n = 3). The slope of the linear fitting corresponds to −k3.
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