Design, Synthesis, <i>In Silico</i> Absorption, Distribution, Metabolism, and Elimination and Molecular Docking Studies of Thiazole‐Based Furan Derivatives, and Their Biological Evaluation for Alzheimer Disease Therapy

Herein, a series of novel 5-hydroxymethylfuran incorporated thiazole-based furan derivatives are synthesized and characterized. The in vitro inhibitory potentials of the derivatives against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are evaluated. In addition, the inhibitory potential of the thiazole-based furan derivatives against AChE (4EY7) and BChE (4BDS) proteins is examined as in silico. For this purpose, the effects of the compounds on human metabolism are evaluated with absorption, distribution, metabolism, excretion, and toxicity programming. Furthermore, their antioxidant potential is assessed through 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging assays. The enzymatic inhibition studies reveal that all compounds exhibit inhibitory effects on both AChE and BChE. Among them, compound 2b demonstrates the most potent inhibition against AChE, with a K_I value of 14.887 ± 1.054 μM, whereas compound 2f exhibits the highest inhibitory activity against BChE, with a K_I value of 4.763 ± 0.321 μM. Compounds 2a (12.202% for DPPH and 56.842% for ABTS) and 2i (13.309% for DPPH and 31.842% for ABTS) are among the most active compounds for both radical scavenging tests. These findings highlight that the synthesized derivatives possess promising dual cholinesterase (ChE) inhibitory activity as well as radical scavenging potential. These activities emphasize their potential as therapeutic candidates for neurodegenerative disorders such as Alzheimer's disease.