## 3 Results and Discussion
### Structure-Activity Relationship (SAR)  
In addition to evaluating the inhibitory activities of **3a-t** against MAOs, AChE, BChE, and BACE-1, we investigated their structures. For the enzyme inhibitory activity against MAO-A (reference compound toxactone; IC\({}_{50}\): 1.08 uM), compound **3a** (IC\({}_{50}\): 1.54 uM) carrying 3-F and the non-substituted compound **3a** (IC\({}_{50}\): 3.35 uM) were found to have the highest activity. Compound **3p** (IC\({}_{50}\): 4.77 uM) carrying 4-F in its structure showed high activity, while compound **3n** carrying 2-F (IC\({}_{50}\): 13.0 uM) showed low activity. The fluorine atom is inductively electron-attracting and resonantly electron-donating. The fluorine atom increased the activity when it is in the meta position but decreased it when it is in the ortho position. This suggests that the addition of fluorine in meta improves the interactions with the enzyme, perhaps participating in halogen bond or favoring conformations for \(\pi\)-stacking. Otherwise, in the ortho position it probably hinders the interaction with the enzyme. For the MAO-B enzyme inhibition activity (reference compound toxactone0.14 uM), the compounds showing the highest activity were the 3-NO\({}_{2}\)-carrying compound **3s** (IC\({}_{50}\): 3.64 uM), the 4-NO\({}_{2}\) derivative compound **3t** (IC\({}_{50}\): 5.69 uM), and the non-substituted compound **3a** (IC\({}_{50}\): 7.69 uM). The activity of compound **3r**, which carries a 2-NO\({}_{2}\) substituent (IC\({}_{50}\): 27.6 uM), was found to be quite low. The higher activity of the compound carrying the nitro group in the meta position (compound **3s**), compared to the non-substituted derivative (compound **3a**), suggested that the inductive effect of nitro played an important role. In addition, the activity of the compound having the nitro substituent in the para position (compound **3t**) was higher than the non-substituted derivative (compound **3a**), but the nitro moiety in the ortho position (compound **3r**) decreased activity. It suggested that the electron donor nitro group in the meta-para position probably increases and enhances the interactions with the enzyme, maybe establishing \(\pi\)-hole interactions or favoring \(\pi\)-stacking; conversely, when the nitro group is in the ortho  
\begin{table}
\begin{tabular}{c c c c c c c c c} \hline \hline \multirow{2}{*}{**Compound**} & \multicolumn{4}{c}{**Residual Activity at 10 uM (\%)**} & \multicolumn{4}{c}{**IC\({}_{50}\) (uM)**} & \multirow{2}{*}{**SI b**} \\ \cline{2-2} \cline{4-9}  & **MAO-A** & **MAO-B** & **ACHE** & **BChE** & **BACE-1** & **MAO-A** & **MAO-B** & **BACE-1** \\ \hline
**3a** & \(0.77\pm 0.36\) & \(36.3\pm 1.63\) & \(82.1\pm 1.19\) & \(53.4\pm 3.75\) & \(83.1\pm 0.61\) & \(3.35\pm 0.22\) & \(7.69\pm 0.27\) & & 0.44 \\  
** & \(18.3\pm 0.47\) & \(34.7\pm 3.61\) & \(79.5\pm 2.24\) & \(76.6\pm 2.87\) & \(72.7\pm 0.28\) & \(6.05\pm 0.33\) & \(5.69\pm 0.47\) & & 1.06 \\ \multicolumn{2}{c}{Toloxatone} & \multirow{position it is possible that it generates a steric hindrance which reduces the interactions with the enzyme. The AChE and BChE enzyme inhibition activities were found to be very low compared with the IC\({}_{50}\) values of the references Tacrine and Donepezil. Compared with Donepezil (IC\({}_{50}\): 0.18 uM), only the non-substituted derivative compound **3a** showed notable inhibitory activity (IC\({}_{50}\): 16.1 uM). These results show that substituents on these compounds inhibit their interaction with the AChE and BChE enzymes. Several compounds effectively inhibited BACE-1 activity. The IC\({}_{50}\) value of the reference compound quercetin was 13.4 uM, and those of **3n**, **3e**, and **3f** were 8.47, 8.63, and 9.92 uM, respectively, which were the lower among the tested compounds. Compound **3n** carries 2-F, **3e** carries 2-OCH\({}_{3}\), and **3f** carries 3-OCH\({}_{3}\). The presence of fluorine or methoxy in the second position of the compound was observed to increase its interaction with the BACE-1 enzyme.