Synthesis, complexation, in vitro cholinesterase inhibitory activities and molecular docking of azinethiacrown ethers and acyclic thiacrown ethers derived indole

Abstract

A series of new thiacrown ethers 14–16, 18–22 and acyclic thiacrown ethers (podands) 31–36 and 52–57 derived indole were synthesized and characterized by NMR and mass spectrometric techniques. Preliminary complexation study of podands 31–36 and 52–54 with some metal cations was studied using a conductometric method in acetonitrile at 25 °C. After the addition of acetonitrile solution of 31–36 or 52–54 podands to the metal cation acetonitrile solutions, the conductance was strongly decreased only in the presence of Hg2+ ions. The order of the stability constants of 1:1 podands–Hg2+ complexes is in the order: 52 > 53 > 35> 31> 32> 36> 33. On the other hand, podands 34 and 54 formed 1:2 podands–Hg2+ complexes.Thiacrown ethers 14–16, 18–22 and acyclic thiacrown ethers 31–36, and 52–57 were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes in vitro. The results indicated that compounds 14–57 demonstrated more potent inhibitory effects on AChE compared to BuChE, with IC50 values ranging from 0.244 to 1.359 mM and 1.270 to 81.473 mM, respectively. Notably, compound 16 most potently inhibited AChE with an IC50 value of 0.244 mM, being 149.6-fold more selective for AChE than BuChE. The presence of imine, ester groups, and sulfur, as well as oxygen or bromine atoms in the cyclic thiacrown ethers, improved their inhibitory activity against both AChE and BuChE.Inhibition of AChE by compounds 19, 20, 54, and 56 ranged from recovery levels of over 50 % to 74.2 %, while inhibition of BuChE by compounds 18, 19, 31, 32, 55, and 56 ranged from 48.2 % to 79.3 %. These findings underscore the potential of azinethiacrown ethers and acyclic thiacrown ethers as promising candidates for further exploration in the context of AChE and BuChE inhibition. In silico molecular docking using the CDocker tool confirmed the mechanism of action of synthetic compound 16 which has been successfully docked into the binding pocket of AChE protein with the highest score of 42.36 in comparison with the rest of the compounds.