Synthesis, Molecular Simulation, DFT, and Kinetic Study of Imidazotriazole-Based Thiazolidinone as Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase Enzymes

Abstract

Background: Alzheimer's disease is a complex and multifactorial brain disorder characterized by gradual memory impairment, cognitive disturbance, and severe dementia, and, ultimately, its progression leads to patient death. This research work presents the design, synthesis, and characterization of novel imidazotriazole-based thiazolidinone derivatives (1-14), displaying promising anti-Alzheimer's activity. Methods: These derivatives were synthesized by using 1H-imidazole-2-thiol as a starting reagent. Structural characterization was accomplished by ¹³C-NMR and ¹H-NMR, while the molecular weight was confirmed by HREI-MS. These compounds were investigated for their anti-Alzheimer's potential under an in vitro analysis. Results: These compounds showed a significant to moderate biological potential against AChE and BChE in comparison to donepezil (IC₅₀ = 8.50 µM and 8.90 µM against AChE and BuChE), used as a reference drug. Among these compounds, analog 10 with IC₅₀ values of 6.70 µM and 7.10 µM against AChE and BuChE emerged as the lead compound of the series with promising biological efficacy against targeted enzymes. Molecular docking revealed the interactive nature of active ligands against target enzymes. These compounds were also assessed under dynamic conditions to examine the structural deviation and conformational changes in a protein complex structure. DFT calculations provided the relative stability and reactivity of the lead compounds. An ADMET analysis showed that these compounds have no toxicological profile. Conclusions: This research study paves the way for the further development and optimization of novel and selective imidazotriazole-based thiazolidinone inhibitors as potent anti-Alzheimer's agents.

Keywords: Alzheimer’s disease; MD simulations; molecular docking; pharmacophore modeling; triazole-thiazolidinone.

Figure 1

Represents the comparison of newly reported compounds and already-reported triazole and thiazolidinone derivatives (rationalization).

Scheme 1

Synthesis of imidazotriazole-based thiazolidinone derivatives (1–14).

Figure 2

Represents structure of analog 10 (Ring A represents varied substituted phenyl ring and ring B represents methoxy substituted phenyl ring.

Figure 3

Percentage inhibition of analog 10 vs. inhibitor concentration, which illustrates the drug–dose relationship against AChE (left) and BChE (right).

Figure 4

Insights into the mechanism of action for analog 10 as competitive inhibitor.

Figure 5

Insights into the mechanism of action for analog 9 as uncompetitive inhibitor.

Figure 6

Insights into the mechanism of action for analog 5 as non-competitive inhibitor.

Figure 7

Docking results for analog 3 (blue), 10 (yellow) and 11 (pink) in AChE complex (binding affinity and interactions).

Figure 8

Docking results for analog 3 (blue), 10 (yellow) and 11 (pink) in BChE complex (binding affinity and interactions).

Figure 9

Represents the Pharmacophore model of analog 10.

Figure 10

Molecular dynamics simulation for analog 10 in targeted protein complex.

Figure 11

Solvation effect on analog 10.

Figure 12

Electrostatic potential surface for analog 3, 10 and 11, illustrating molecular arrangement and electrophilic as well as nucleophilic regions.

Figure 13

Molecular orbital analysis of analog 3, 10 and 11: Visualization of HOMO and LUMO orbitals, orbital lobes and their respective energies.