Thieno-Thiazolostilbenes, Thienobenzo-Thiazoles, and Naphtho-Oxazoles: Computational Study and Cholinesterase Inhibitory Activity

Abstract

Naphtho-triazoles and thienobenzo-triazoles have so far proven to be very potent inhibitors of the enzyme butyrylcholinesterase (BChE). Based on these results, in this work, new thienobenzo-thiazoles were designed and synthesized, and their potential inhibitory activity was tested and compared with their analogs, naphtho-oxazoles. The synthesis was carried out by photochemical cyclization of thieno-thiazolostilbenes obtained in the first reaction step. Several thienobenzo-thiazoles and naphtho-oxazoles have shown significant potential as BChE inhibitors, together with the phenolic thiazolostilbene being the most active of all tested compounds. These results are significant as BChE has been attracting growing attention due to its positive role in the treatment of Alzheimer's disease. Computational examination based on the DFT approach enabled the characterization of the geometry and electronic structure of the studied molecules. Furthermore, the molecular docking study, accompanied by additional optimization of complexes ligand-active site, offered insight into the structure and stabilizing interactions in the complexes of studied molecules and BChE.

Keywords: 1,3-oxazole; 1,3-thiazole; cholinesterase inhibition; electronic structure; molecular docking; thiophene.

Figure 1

Previous (a) and current (b) structures of interest as cholinesterase inhibitors.

Scheme 1

Reaction pathway for the synthesis of thieno-thiazolostilbenes 1a–10a and thienobenzo-thiazoles 1–5, 7, and 9. Percentages in parentheses represent yields in reactions for compounds 1a–10a, 7, and 9, and isolated yields for compounds 1–5.

Figure 2

Crucial parts of the ¹H NMR spectra of trans-8a (a), trans-1a (b), and 1 (c).

Figure 3

UV spectra (ACN) of thiazolostilbenes trans-2a, trans-3a, and trans-10a (left); and cis-1a, trans-1a and their electrocyclization product 1 (right).

Figure 4

The most stable conformers of isolated cis- and trans-isomers of thieno-thiazolostilbenes. Geometries are optimized at M062X/6-31G(d) level of theory.

Figure 5

The geometries of isolated thienobenzo-thiazoles 1–5, optimized at M062X/6-31G(d) level of theory.

Figure 6

Canonical orbitals involved in main transitions in calculated spectra of compound 1.

Figure 7

Canonical orbitals involved in main transitions in calculated spectra of compounds 3 (a) and 4 (b).

Figure 8

Dose–response curve for the inhibition of BChE by 1 (a), 3 (b), and 4 (c).

Figure 9

Dose–response curve for the inhibition of BChE by trans-1a (a) and trans-8a (b).

Figure 10

The optimized complex structure between the active site of BChE and molecule 4. Distances are given in angstroms. Hydrogen atoms of residues are not shown for clarity.

Figure 11

The optimized complex structure between the active site of BChE and molecule 15. Distances are given in angstroms. Hydrogen atoms of residues are not shown for clarity.

Figure 12

The optimized structures of the complex between trans-8 and the active site of BChE. (a) The structure obtained by optimizing the docked compound’s geometry with the lowest binding energy from the most populated cluster, and (b) the optimized complex’ structure obtained from the starting geometry of docked compound with the lowest binding energy from the second most populated cluster. Distances given in angstroms. The ligand is presented with a ball and sticks model. Hydrogens of the residues omitted for clarity.