Grid‐Type Quaternary Metallosupramolecular Compounds Inhibit Human Cholinesterases through Dynamic Multivalent Interactions

Abstract

We report the implementation of coordination complexes containing two types of cationic moieties, i. e. pyridinium and ammonium quaternary salt, as potential inhibitors of human cholinesterase enzymes. Utilization of ligands containing NNOcoordination site and binding zinc metal ion allowed monoand tetra-nuclear complexes to be obtained with corner and grid structural type, respectively, thus affecting the overall charge of the compounds (from + 1 to + 8). We were able to examine for the first time the multivalency effect of metallosupramolecular species on their inhibitory abilities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Importantly, resolution of the crystal structures of the obtained enzyme-substrate complexes provided a better understanding of the inhibition process at the molecular level.

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

“…Yield 96%. 1 (15). Aldehyde 3 (80 mg; 0.377 mmol); 1-(3,4dimethoxyphenyl)methanamine (57 μl; 0.377 mmol); NaBH 4 (13 mg; 0.339 mmol) in MeOH (5 mL).…”

“…Yield 93%. 1 {[3-(Benzyloxy)phenyl]methyl}(3-phenylpropyl)amine (17). Aldehyde 3 (80 mg; 0.377 mmol); 3-phenylpropan-1-amine (54 μl; 0.377 mmol); NaBH 4 (13 mg; 0.339 mmol) in MeOH (5 mL).…”

“…Yield 99%. 1 (28). Aldehyde 27 (100 mg; 0.471 mmol); tyramine (65 mg; 0.471 mmol); NaBH 4 (16 mg; 0.424 mmol) in MeOH (5 mL).…”

“…Yield 34%. 1 H NMR (500 MHz, CDCl 3 ) δ: 7.46-7.37 (m, 4H), 7.37-7.31 (m, 1H), 7.22-7.17 (m, 2H), 7.02-6.97 (m, 2H), 6.95-6.89 (m, 2H), 6.70-6.65 (m, 2H), 5.04 (s, 2H), 4.71 (bs, 1H), 3.76 (s, 2H), 2.89 (t, J = 6.9 Hz, 2H), 2.77 (t, J = 6.9 Hz, 2H). 13 (31).…”

“…Yield 88%. 1 (5 mL). After evaporation, the residue was purified by preparative TLC using mobile phase cHx/DEA (9 : 1.5) to get pure product 37 as a yellow oil.…”