Synthesis and molecular docking studies of novel thiazole derivatives as multi-target inhibitors against Alzheimer’s Disease

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by a severe decline in cognitive function and memory impairment. Its complex etiology, primarily driven by interconnected mechanisms such as cholinergic deficits and oxidative stress, renders conventional single-target therapies inadequate. This limitation highlights the urgent need for Multi-Target-Directed Ligands (MTDLs) capable of modulating diverse pathological pathways simultaneously [1,2]. The 1,3-thiazole scaffold has emerged as a highly versatile pharmacophore in medicinal chemistry. However, achieving potent and balanced dual inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) alongside robust antioxidant capacity within a single molecular framework remains a formidable challenge. To address this critical gap, we implemented a rational drug design strategy to develop a novel series of MTDLs. By structurally hybridizing a central 1,3-thiazole ring with a hydrazone linker and a (methylthio)phenyl moiety, we aimed to create highly potent agents with synergistic therapeutic profiles against AD.

Methods

The novel series of 1,3-thiazole derivatives was successfully synthesized utilizing the Hantzsch reaction methodology [3]. The chemical structures of all synthesized compounds were rigorously elucidated through comprehensive techniques, including IR and NMR spectroscopy, high-resolution mass spectrometry (HRMS), and elemental analysis. The in vitro biological evaluation assessed the multi-target potential of the derivatives. Inhibitory activities against AChE and BChE were determined, while the antioxidant capacity was evaluated exclusively using the DPPH radical scavenging assay. Furthermore, in silico molecular docking studies were executed utilizing advanced computational platforms (Schrödinger Maestro) [4] to elucidate precise binding interactions within the enzymatic active sites. Computational ADME predictions were also conducted via SwissADME [5] to evaluate the pharmacokinetic profiles and overall drug-likeness.

Results

In vitro evaluations revealed highly promising multi-target profiles. In the DPPH assay, specific derivatives, notably compounds 1 and 8, exhibited remarkable radical scavenging activities, underscoring their potential to combat oxidative stress. Regarding cholinesterase inhibition, compound 3, incorporating a distinctive 4-chlorophenyl moiety, emerged as the most exceptional derivative. Impressively, compound 3 displayed a 23-fold higher inhibitory activity against AChE and a 10-fold greater activity against BChE compared to the clinical reference drug, donepezil. Detailed enzyme kinetic studies further confirmed that compound 3 functions as a potent competitive inhibitor. These compelling in vitro findings were robustly supported by in silico evaluations. Molecular docking demonstrated that compound 3 establishes strong, thermodynamically favorable binding interactions within the catalytic active sites of the target enzymes. Moreover, ADME predictions confirmed its strict adherence to universally accepted drug-likeness criteria, including Lipinski’s and Veber’s rules, ensuring an optimal pharmacokinetic profile.

Conclusions

By successfully mapping the in vitro and computational profiles of these novel derivatives, this study provides compelling evidence that concurrently targeting cholinergic deficits and oxidative stress is a highly achievable strategy. With its remarkable dual cholinesterase inhibition, favorable binding interactions, and optimal pharmacokinetic properties, compound 3 distinguishes itself as a robust lead candidate for advanced pre-clinical investigations in Alzheimer’s disease.

References

1. .Moreira, N., Lima, J., Marchiori, M.F., Carvalho, I., Sakamoto-Hojo, E.T., 2022. Neuroprotective Effects of Cholinesterase Inhibitors: Current Scenario in Therapies for Alzheimer’s Disease and Future Perspectives. J Alzheimers Dis Rep 6:177–93, https://doi.org/10.3233/adr-210061
2. .Begines, P., Fernández-Bolaños, J.G., López, Ó., 2026. An updated patent review of acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease (2021–present). Expert Opinion on Therapeutic Patents 36:159–90, https://doi.org/10.1080/13543776.2025.2602702
3. .Hantzsch, A., Weber, J.H., 1887. Ueber Verbindungen des Thiazols (Pyridins der Thiophenreihe). Berichte der deutschen chemischen Gesellschaft 20:3118–32, https://doi.org/10.1002/cber.188702002200
4. . Schrödinger Release 2024-3: Maestro, Schrödinger, LLC, New York, NY, USA, 2024.
5. .Daina, A., Michielin, O., Zoete, V., 2017. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports 7:42717, https://doi.org/10.1038/srep42717