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. 2024 Jul 6;14(1):15577.
doi: 10.1038/s41598-024-66424-z.

Synthesis, biological evaluation, molecular docking, and MD simulation of novel 2,4-disubstituted quinazoline derivatives as selective butyrylcholinesterase inhibitors and antioxidant agents

Sara Sadeghian  1 , Raziyeh Razmi  1 , Soghra Khabnadideh  1   2 , Mehdi Khoshneviszadeh  1 , Pegah Mardaneh  1   3 , Arman Talashan  1 , Arman Pirouti  1 , Fatemeh Khebre  1 , Zahra Zahmatkesh  1 , Zahra Rezaei  4   5
Affiliations

Synthesis, biological evaluation, molecular docking, and MD simulation of novel 2,4-disubstituted quinazoline derivatives as selective butyrylcholinesterase inhibitors and antioxidant agents

Sara Sadeghian et al. Sci Rep. .

Abstract

Alzheimer's disease is the most prevalent neurodegenerative disorder characterized by significant memory loss and cognitive impairments. Studies have shown that the expression level and activity of the butyrylcholinesterase enzyme increases significantly in the late stages of Alzheimer's disease, so butyrylcholinesterase can be considered as a promising therapeutic target for potential Alzheimer's treatments. In the present study, a novel series of 2,4-disubstituted quinazoline derivatives (6a-j) were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes, as well as for their antioxidant activities. The biological evaluation revealed that compounds 6f, 6h, and 6j showed potent inhibitory activities against eqBuChE, with IC50 values of 0.52, 6.74, and 3.65 µM, respectively. These potent compounds showed high selectivity for eqBuChE over eelAChE. The kinetic study demonstrated a mixed-type inhibition pattern for both enzymes, which revealed that the potent compounds might be able to bind to both the catalytic active site and peripheral anionic site of eelAChE and eqBuChE. In addition, molecular docking studies and molecular dynamic simulations indicated that potent compounds have favorable interactions with the active sites of BuChE. The antioxidant screening showed that compounds 6b, 6c, and 6j displayed superior scavenging capabilities compared to the other compounds. The obtained results suggest that compounds 6f, 6h, and 6j are promising lead compounds for the further development of new potent and selective BuChE inhibitors.

Keywords: Antioxidant; Cholinesterase inhibitors; MD simulation; Molecular docking; Quinazoline.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
The chemical structures of the AChE inhibitor drugs currently used in Alzheimer's treatment.
Figure 2
Figure 2
Synthesis of 2,4-disubstituted quinazoline derivatives 6a–j. Reagents and conditions: (a) 190 °C, 24 h; (b) POCl3, N,N-diethylaniline, 115 °C, 16 h; (c) EtOH, reflux, 24 h.
Figure 3
Figure 3
(A) Lineweaver–Burk plot for the inhibition of eelAChE by compound 6h; (B) Lineweaver–Burk plot for the inhibition of eqBuChE by compound 6f.
Figure 4
Figure 4
2D and 3D interactions of compounds 6f, 6h, and 6j in the active site of BuChE (1P0I). (Green: Van der Waals, light green: carbon hydrogen bond, dark green: hydrogen bond, dark pink: π−π, light pink: alkyl & π-alkyl, purple: π-sigma, orange: π-sulfur).
Figure 5
Figure 5
The RMSD analysis of a complex involving the compound 6f interacting with the hBuChE indicated that 6f stabilized inside the hBuChE after 10 ns of simulation.
Figure 6
Figure 6
The assessment of RMSF value was performed on the complex involving the compound 6f.
Figure 7
Figure 7
The radius of gyration (Rg) plot of compound 6f in the equilibrium time range.
Figure 8
Figure 8
The stability of hydrogen bond interactions between 6f and promising residues inside the active site of hBuChE in the equilibrium time range.
Figure 9
Figure 9
Molecular dynamics (MD) simulation analysis of 6f with hBuChE.
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