Charged Thienobenzo-1,2,3-Triazoles as Especially Potent Non-Selective Cholinesterase Inhibitors: Design, Anti-Inflammatory Activity, and Computational Study

Abstract

Background/Objectives: This research reports the synthesis and evaluation of novel charged thienobenzo-triazoles as non-selective cholinesterase inhibitors (AChEs and BChEs), their anti-inflammatory properties, and a computational study. Methods: Fifteen derivatives were created through photochemical cyclization and quaternization of the triazole core. The compounds were tested for AChE and BChE inhibition. They showed greater potency and selectivity toward BChE. Results: The most potent compound, derivative 14, inhibited BChE with an IC₅₀ of 98 nM, while derivative 9 also displayed significant anti-inflammatory activity by inhibiting LPS-induced TNF-α production (IC₅₀ = 0.66 µM). Molecular docking revealed that triazolinium salts form key π-π and electrostatic interactions within enzyme active sites. In silico predictions indicated favorable ADME-Tox properties for compounds 9 and 11, including low mutagenicity and moderate CNS permeability. Conclusions: These findings highlight the potential of new charged triazolinium salts as peripherally selective cholinesterase inhibitors with additional anti-inflammatory potential.

Keywords: ADME-Tox prediction; BChE inhibitors; anti-inflammatory activity; cholinesterase; molecular docking; thienobenzo-1,2,3-triazoles.

Figure 1

Structures of uncharged thienobenzo-triazoles I with preferred inhibition of BChE and their charged triazolinium salts II as dual cholinesterase inhibitors [19].

Scheme 1

Synthetic steps to charged triazolinium benzyl salts 1–15.

Figure 2

Structures of new charged thienobenzo-1,2,3-triazolinium salts 1–15 and their isolated yields in brackets.

Figure 3

Parts of the ¹H NMR spectra of charged triazolinium salts (a) 9, (b) 11, and (c) 1.

Figure 4

Inhibition of LPS-stimulated TNFα production in PBMCs from two donors for charged triazolinium bromide salt 9.

Figure 5

(a) The structure of triazolinium salt 9 docked into the active site of AChE. (b) Structure of triazolinium salt 11 docked into the active site of AChE. Ligands are presented using a ball-and-stick model, with distances given in angstroms.

Figure 6

(a) The structure of triazolinium salt 9 docked into the active site of BChE. (b) Structure of triazolinium salt 11 docked into the active site of BChE. Ligands are presented using a ball-and-stick model, with distances given in angstroms.