Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase

We present the synthesis and characterization of merged human butyrylcholinesterase (hBChE) inhibitor/cannabinoid receptor 2 (hCB2R) ligands for the treatment of neurodegeneration. In total, 15 benzimidazole carbamates were synthesized and tested for their inhibition of human cholinesterases, also with regard to their pseudoirreversible binding mode and affinity toward both cannabinoid receptors in radioligand binding studies. After evaluation in a calcium mobilization assay as well as a β-arrestin 2 (βarr2) recruitment assay, two compounds with balanced activities on both targets were tested for their immunomodulatory effect on microglia activation and regarding their pharmacokinetic properties and blood–brain barrier penetration. Compound 15d, containing a dimethyl carbamate motif, was further evaluated in vivo, showing prevention of Aβ25–35-induced learning impairments in a pharmacological mouse model of Alzheimer’s disease for both short- and long-term memory responses. Additional combination studies proved a synergic effect of BChE inhibition and CB2R activation in vivo.

show abstract

“…All procedures used to determine the binding properties of the inhibitors on ChEs have been established before. ,,,,,,− …”

Section: Methodsmentioning

confidence: 99%

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

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…ChEs are therapeutic targets for the symptomatic treatment of Alzheimer's disease (AD) since these enzymes hydrolyze the neurotransmitter acetylcholine, whose level is low in AD patients [43] . Few examples of guanidine‐containing molecules exhibiting cholinesterase inhibitory ability were reported [16,17,44] . Moreover, we have previously found the inhibitory effects of aminopurine and guanine isonucleosides on the activity of acetylcholinesterase, [45,46] which further motivated us to evaluate the anticholinesterasic activities of simpler guanidine‐containing sugar derivatives such as the synthesized 5‐guanidino furanoses.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives**

et al. 2022

View full text Add to dashboard Cite

The synthesis and biological evaluation of novel guanidino sugars as isonucleoside analogs is described. 5‐Guanidino xylofuranoses containing 3‐O‐saturated/unsaturated hydrocarbon or aromatic‐containing moieties were accessed from 5‐azido xylofuranoses via reduction followed by guanidinylation with N,N′‐bis(tert‐butoxycarbonyl)‐N′′‐triflylguanidine. Molecules comprising novel types of isonucleosidic structures including 5‐guanidino 3‐O‐methyl‐branched N‐benzyltriazole isonucleosides and a guanidinomethyltriazole 3′‐O‐dodecyl xylofuranos‐5′‐yl isonucleoside were accessed. The guanidinomethyltriazole derivative and a 3‐O‐dodecyl (N‐Boc)guanidino xylofuranose were revealed as selective inhibitors of acetylcholinesterase (Ki=22.87 and 7.49 μM, respectively). The latter also showed moderate antiproliferative effects in chronic myeloid leukemia (K562) and breast cancer (MCF‐7) cells. An aminomethyltriazole 5’‐isonucleoside was the most potent molecule with low micromolar GI50 values in both cells (GI50=6.33 μM, 8.45 μM), similar to that of the drug 5‐fluorouracil in MCF‐7 cells. Moreover, the most bioactive compounds showed low toxicity in human fibroblasts, further indicating their interest as promising lead molecules.

show abstract

“…All procedures used to determine the binding properties of the inhibitors on ChEs have been established before. 19,20,24,26,27,37,[43][44][45][46][47][48]…”

Section: Cholinesterase Inhibitionmentioning

confidence: 99%

Novel benzimidazole-based pseudo-irreversible butyrylcholinesterase inhibitors with neuroprotective activity in an Alzheimer's disease mouse model

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase

Cited by 17 publications

References 50 publications

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

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

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives**

Novel benzimidazole-based pseudo-irreversible butyrylcholinesterase inhibitors with neuroprotective activity in an Alzheimer's disease mouse model

Contact Info

Product

Resources

About