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

Abstract

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 K_i = 41.41 ± 2.53 nM; α-amylase IC₅₀ = 1.25 ± 0.02 nM), 3h (α-glucosidase K_i = 44.19 ± 2.41 nM; α-amylase IC₅₀ = 2.87 ± 0.16 nM and acrabose (α-glucosidase K_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 K_i = 59.71 ± 2.24 nM; BChE K_i = 8.43 ± 0.97 nM), 4i (AChE K_i = 53.31 ± 1.74 nM; BChE K_i = 10.72 ± 2.19 nM), and tacrine (AChE K_i = 132.35 ± 5.90 nM; BChE K_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, in silico 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.