In this study, we aimed to design novel and less hepatotoxic THA-derived MTDLs to target dysfunctions in both the cholinergic and glutamatergic systems. To this end, we synthesized 16 THA derivatives and evaluated their inhibitory potency against cholinesterases (ChEs), specifically AChE and butyrylcholinesterase (BChE; EC 3.1.1.8). In adition, chromatographic techniques were employed to examine specific physico-chemical characteristics, including lipophilicity, the binding of drugs to plasma proteins, and affinity for phospholipids. Furthermore, we have screened the compounds for their ability to cross the blood-brain barrier (BBB) and assessed their potential cytotoxicity on the human hepatocyte carcinoma (HepG2) cell line. Based on the results, we identified the most promising candidates and further examined their microsomal stability, effects on NMDAR antagonism, dehydrogenase activity, and glutathione levels. Following a down-selection process, compound 5m emerged as the lead candidate and progressed to an in vivo pharmacokinetic (PK) study.