From bench to brain: novel thieno-oxazine hybrids as potent pleiotropic anti-Alzheimer’s agents with <i>in vivo</i> / <i>in vitro</i> validation and <i>in silico</i> 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-4<i>H</i>-benzo[4,5]thieno[3,2-<i>e</i>][1,3]oxazin-4-one <b>(9-14)</b> was synthesised starting from cyclohexa[<i>b</i>]thiophene. Compounds <b>9</b> and <b>10</b> 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 <b>9</b> and <b>10</b> 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 <b>5</b> and <b>11</b> demonstrated higher selectivity towards BChE (SI < 1). <i>In-silico</i> ADMET calculations as well as molecular docking have been performed for synthetic compounds.