AChE inhibition remains pivotal to AD symptomatic therapy. As the disease progresses, AChE levels decline, whereas BChE levels remain stable or may slightly increase as a compensatory mechanism to counteract the loss of neuronal AChE activity . For these reasons, we have established the inhibition activity against both human AChE (hAChE) and human BChE (hBChE). The modified spectrophotometric method of Ellman et al. was applied to assess the inhibitory potency of the novel compounds. THA and 7-PhO-THA were used as reference compounds. The IC50 values of all tested derivatives and their selectivity index (SI) for hAChE are summarized in Table . All compounds effectively inhibited both types of ChEs at the micromolar range. The IC50 values ranged from 0.160 μM (5i) to 1.179 μM (5a) and 0.059 μM (7) to 2.475 μM (5g) for hAChE and hBChE, respectively. The derivatives of THA substituted with pyridine (5a-5d) displayed a non-selective inhibition pattern. Among these, compound 5c, bearing 6-chloropyridine at position 7 of the THA scaffold, demonstrated the highest inhibitory potency. In contrast, compound 5a, containing an unsubstituted pyridine, exhibited the weakest activity within this group. In the pyrimidine series (5e-5g), structural variations on the pyrimidine core had a negligible impact on inhibitory potency. This was exemplified by derivative 5e endowed with unsubstituted pyrimidine, which exhibited the highest level of BChE inhibition within the subset. For compounds containing a furan moiety (5h-5i), substitution with a methyl group on the furan ring significantly enhanced potency. Indeed, compound 5i was ten times more effective against AChE and twice as potent against BChE than 5h. Notably, derivative 5i emerged as the most effective AChE inhibitor (hAChE IC50 = 0.160 µM) among the entire (hetero)aryl-THA series. Similarly, substitution with a thiophene group at position 7 of the THA scaffold produced derivatives 5j-5m, with 5m exhibiting the strongest inhibition against both enzymes. In fact, compound 5m was the most effective BChE inhibitor (hBChE IC50 = 0.165 µM) within the (hetero)aryl-THA series. The aryl-THA derivatives 5n and 5o exhibited comparable IC50 values, similar to those of 5k and 5b. Overall, substitution with a five-membered heteroaryl ring generally led to more potent inhibition than substituting with a six-membered ring. The deuterated THA analogue 7 displayed inhibitory activity closely resembling that of THA, as expected, given the minimal structural modification. Nonetheless, compound 7 emerged as the most potent BChE inhibitor (hBChE IC50 = 0.059 µM) among all the newly synthesized derivatives. All compounds, except for 5i and 7, exhibited lower inhibitory activity relative to THA. Nevertheless, all newly developed derivatives showed markedly greater inhibitory potency than the reference molecule 7-PhO-THA.