## 3 Conclusions and Perspectives  
AD is the most common single cause of dementia and has become a worldwide health concern [67]. Thus, increasing efficacy and limiting side effects in managing AD is a priority. Complex pathogenesis prompted medicinal chemists to search for dual or multiple target drugs with the aim of generating a synergistic therapeutic effect, going beyond conventional AChE inhibitors [9]. Compounds acting at the same time on other targets or mechanisms, such as A\(\upbeta\) aggregation, BuChe and oxidative stress, were studied through the years. Most importantly, reports in the literature demonstrated that the combined use of cholinesterase and PDE inhibitors, in particular, could turn out to have a different, complementary effect on early and late long-term potentiation (LTP) of cognitive function [7]. This strategy is also recently being pursued in the field of synthetic medicinal chemistry, with the development of drug-like small molecules targeting PDE5 and AChE [9] and in the context of drug repurposing, as in the case of the well-known drug tadalafil [8; 68; 69]. The field of dual cholinesterase-PDE inhibitors attracts great interest in developing novel tools against dementia and has been previously investigated from the point of view of the underlying  
Figure 5: Chemical structures of representative polyphenic acids detected in the investigated extracts. biochemical mechanisms and synergistic effects promoted by the inhibition of these two enzymes. More specifically, [PERSON] et al. reported that AChE and PDE5 inhibitors affect memory processes at different extents. In particular, PDE5 inhibitors improve consolidation of object information, while AChE inhibitors induce a different outcome by improving processes of acquisition of object information [70]. Moreover, PDE5 inhibitors can stimulate the neurogenesis and, thus, dual inhibitors potentially produce synergistic effects on AD [71]. From a chemical point of view, compounds acting on these two targets must be endowed with some specific features which may be deduced from the available structures of AChE and PDEs and of their complexes with ligands. As depicted in Figure 1b, tadalafil interacts with PDE5 through a pool of hydrophobic residues (Ala767, Ile778, Ala779, Ala783, Phe787, Phe786, Ile813, Phe820), but also via some polar amino acids, such as Gln775 and Gln817. Interestingly, a similar interaction pattern with PDE5 is shared by icarisid II, which binds the identical region of PDE5, mainly through the same hydrophobic residues (Leu725, Ala783, Phe786, Phe820; Figure 3). Thus, the presence of an aromatic and hydrophobic portion in the small molecule appears to be mandatory to target this enzyme. Similarly, in the structure of the donepezil-AChE complex (Figure 1a), the ligand interacts with the target via hydrophobic amino acids (Phe295, Phe297, Phe338). Nevertheless, a more polar region can be also identified in the binding site (Tyr72, Asp74, Trp86, Glu202, His447). Thus, even if the two binding sites share some structural similarities, AChE also requires the presence of polar moieties. These features must be taken into account in the design and optimization of dual inhibitors. In the field of natural and Nature-inspired compounds, polypharmacology and synergistic effects are two established milestones. This especially holds true when plant extracts are considered, in which the entourage effect of different chemicals on several biological targets and biochemical pathways often lays the basis for the observed therapeutic outcome. Nevertheless, in the context of dementia, it must be pointed out that the macromolecular targets of such small molecules are located in the CNS, beyond the BBB. This highlights the primary relevance of the pharmacokinetic properties of the studied natural and Nature-inspired compounds since drug-likeness requirements are even stricter in this case.