From bench to brain: novel thieno-oxazine hybrids as potent pleiotropic anti-Alzheimer’s agents with in vivo / in vitro validation and in silico insights

Due to their various pharmacological effects, several substituted sulphur heterocycles containing thiophene have recently attracted a great deal of attention. A novel 2,3-diaryl-2,3,5,6,7,8-hexahydro-4H-benzo[4,5]thieno[3,2-e][1,3]oxazin-4-one (9–14) was synthesised starting from cyclohexa[b]thiophene. Compounds 9 and 10 showed the greatest gene expression downregulation of BAX by 75.1% and 79.7%, and upregulation of Bcl-2 gene expression by 8.1 folds for each. It also decreased the level of AChE by 70.2 and 75%; respectively. Compounds 9 and 10 significantly increased Wnt3a levels by 5.8 and 6.6 folds, and β-Catenin levels by 10.1 and 10.5 folds, respectively, compared to donepezil. They significantly downregulated 5-GSK3β gene expression by 77.1%, and 78.7%, respectively. Even though all compounds exhibited potent inhibition of AChE, all synthesised compounds, except for compounds 5 and 11 demonstrated higher selectivity towards BChE (SI < 1). In-silico ADMET calculations as well as molecular docking have been performed for synthetic compounds.