2-Oxoindolin-thiazoline hybrids as scaffold-based therapeutics for T2DM-associated cognitive impairment: design, synthesis, <i>in vitro</i> and <i>in silico</i> studies

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are closely linked neurodegenerative and metabolic disorders, sharing overlapping pathological mechanisms. In this study, structure-based drug design combined with molecular hybridization strategies was employed to develop dual-acting compounds targeting both conditions. A series of twenty hybrid molecules, comprising 2-oxoindolin-3-thiosemicarbazones (3a-i) and thiazolines (4a-k) were successfully synthesized and characterized using spectroscopic techniques and elemental analysis. Biological evaluations demonstrated that compounds 3d and 3h exhibit potent inhibitory activity against α-glucosidase (α-Glu) and α-amylase (α-Amy), surpassing the efficacy of acarbose. These findings highlight their promising antidiabetic potential and support further investigation into their therapeutic relevance for AD and T2DM comorbidity (3d (α-glucosidase <i>K</i> _i = 41.41 ± 2.53 nM; α-amylase IC₅₀ = 1.25 ± 0.02 nM), 3h (α-glucosidase <i>K</i> _i = 44.19 ± 2.41 nM; α-amylase IC₅₀ = 2.87 ± 0.16 nM and <b>acrabose</b> (α-glucosidase <i>K</i> _i = 101.20 ± 7.53, α-amylase IC₅₀ 9.73 ± 0.20). Furthermore, compounds 3i and 4i exhibited significantly higher inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) compared to the reference drug tacrine. Notably, compound 4i demonstrated exceptional multi-enzyme inhibition, with kinetic parameters indicating strong binding affinity: 3i (AChE <i>K</i> _i = 59.71 ± 2.24 nM; BChE <i>K</i> _i = 8.43 ± 0.97 nM), 4i (AChE <i>K</i> _i = 53.31 ± 1.74 nM; BChE <i>K</i> _i = 10.72 ± 2.19 nM), and <b>tacrine</b> (AChE <i>K</i> _i = 132.35 ± 5.90 nM; BChE <i>K</i> _i = 137.42 ± 4.01 nM). Molecular docking and dynamics simulations corroborated these findings by revealing stable and favorable interactions within the active sites of both enzymes. Additionally, <i>in silico</i> ADME profiling indicated desirable pharmacokinetic properties, further supporting the therapeutic potential of these compounds as dual-action agents for the management of Alzheimer's disease and type 2 diabetes mellitus.