New Thienobenzo/Naphtho-Triazoles as Butyrylcholinesterase Inhibitors: Design, Synthesis and Computational Study

Abstract

This study aims to test the inhibition potency of new thienobenzo/naphtho-triazoles toward cholinesterases, evaluate their inhibition selectivity, and interpret the obtained results by molecular modeling. The synthesis of 19 new thienobenzo/naphtho-triazoles by two different approaches resulted in a large group of molecules with different functionalities in the structure. As predicted, most prepared molecules show better inhibition of the enzyme butyrylcholinesterase (BChE), considering that the new molecules were designed according to the previous results. Interestingly, the binding affinity of BChE for even seven new compounds (1, 3, 4, 5, 6, 9, and 13) was similar to that reported for common cholinesterase inhibitors. According to computational study, the active thienobenzo- and naphtho-triazoles are accommodated by cholinesterases through H-bonds involving one of the triazole's nitrogens, π-π stacking between the aromatic moieties of the ligand and aromatic residues of the active sites of cholinesterases, as well as π-alkyl interactions. For the future design of cholinesterase inhibitors and search for therapeutics for neurological disorders, compounds with a thienobenzo/naphtho-triazole skeleton should be considered.

Keywords: 1,2,3-triazoles; cholinesterases; inhibition; photochemistry; synthesis.

Figure 1

Previously investigated thienobenzo/naphtho-triazoles (A–D) with cholinesterase inhibitory activity.

Scheme 1

Reaction pathway for the synthesis of naphtho-triazoles 1 and 2 [21] and thienobenzo-triazoles 3–6. Numbers given in parentheses represent isolated yields.

Scheme 2

Reaction pathway for the synthesis of thienobenzo-triazoles 4, 7–12 and their non-aromatized precursors 13–19 (Numbers given in parentheses represent isolated yields.).

Figure 2

Comparison of the ¹H NMR spectra (CDCl₃) of investigated compounds (a) 17; (b) 10; (c) 16; (d) 9.

Figure 3

Structure of the active site of AChE docked with naphtho-triazole 1 (a) and thienobenzo-triazole 4 (b). Molecules of the potential inhibitors are presented using a ball-and-stick model.

Figure 4

The structure of the complex between compound 17 (presented with a ball-and-stick model) and the active site of AChE. Hydrogens of the enzyme residues are omitted for clarity.

Figure 5

Structure of the active site of BChE docked with naphtho-triazole 1 (a) and thienobenzo-triazole 4 (b). Molecules of the potential inhibitors are presented using a ball-and-stick model.

Figure 6

The structure of the complex between compound 9 (presented with a ball-and-stick model) and the active site of BChE. Hydrogens of the enzyme residues omitted for clarity.

Figure 7

ORTEP-3 diagrams of two symmetry-independent molecules of 5.

Figure 8

(a) Overlay of molecules A (red) and B (blue); (b) Crystal packing viewed approximately in the direction of the axis a. Molecules A are red, B are blue, and short intermolecular contacts (weak hydrogen bonds and π-stacking) are shown as cyan-dotted lines.