## 2 Multi-Target Natural and Nature-Inspired Compounds
### Xanthines and Other Alkaloids  
Xanthines, including caffeine and caffeine-derived compounds, such as synthetic derivatives, represent outstanding examples of alkaloids modulating many different biochemical pathways in humans (Figure 2) [25; 26]. Caffeine itself, found in _Coffea arabica_ and _C. canephora_, has been referred to as a multi-target compound for decades, in light of its polypharmacological effects [26]. In fact, besides its primary activity on adenosine receptors, caffeine interferes with other neurotransmission systems, including the pathways mediated by acetylcholine, epinephrine, serotonin, dopamine and glutamate [27; 28; 29]. More specifically, in the context of the cholinergic system, caffeine acts as a non-competitive AChE inhibitor (\(\text{K}_{\text{i}}=175~{}\upmu\text{M}\)). This mechanism may be involved in its neuroprotective and anti-inflammatory effects [26]. On the other hand, it has also been reported that caffeine can interfere with intracellular cAMP and cGMP levels by acting as a weak, non-specific reversible PDE inhibitor (\(\text{IC}_{50}=500\text{--}1000~{}\upmu\text{M}\)) [25; 30]. On this basis, caffeine is defined as a \"cognitive enhancer\", and a role for this alkaloid in the modulation of cognitive decline in AD has been proposed. Nevertheless, it must be pointed out that the anti-inflammatory effect on neuro-inflammation conditions may also play a role [31; 32; 33]. Moreover, it has been reported that caffeine has an effect on delaying onset and progression of Parkinson's disease (PD), while it is interestingly negatively implicated in [PERSON]'s disease (HD) [34; 35]. On the side of synthetic derivatives of xanthines being studied as potential tools against neurodegeneration, propertofylline (Figure 2) received great attention. More specifically, this compound was reported to improve cognition and dementia severity in mild-to-moderate AD in clinical trials. Propertofylline is known to target biochemical pathways mediated by PDEs, but other mechanisms have also been proposed. In particular, regulation of genes involved in the onset and progression of oxidative stress, lipid homeostasis, which may interfere with neuronal function, appears to be involved [36; 37]. Moreover, propertofylline inhibits AChE in the \(\upmu\text{M}\) range (\(\text{IC}_{50}=6.40~{}\upmu\text{M}\)) [38]. Pyrazolopyrimidine, which are structurally related to naturally occurring xanthines, were also studied as selective PDE9 inhibitors for the discovery of novel compounds to contrast dementia. In these studies, compound showing inhibitory activities against PDE9 in the nM range were identified (\(\text{IC}_{50}\) values \(<200~{}\upmu\text{M}\)) [39; 40]. On a similar basis, 3-isobutyl-1-methylanthine (IBMX) was previously highlighted as a non-selective inhibitor targeting PDE9 as well as other isoforms in the \(\upmu\text{M}\) range (\(\text{IC}_{50}=230~{}\upmu\text{M}\) for PDE9) [41]. Pyrazolopyridine is another xanthine-inspired scaffold that has been recently considered for the development of dual cholinesterase-PDE inhibitors since such compounds are known to target peripheral anionic binding sites (PAS) of AChE. [PERSON] et al. reported the synthesis of tacrine-pyrazolopyridine hybrid derivatives targeting AChE, butyrylcholinesteraseerase (BuChE), another enzyme involved in sustaining cholinergic tone, and PDE4D. The compounds demonstrated \(\upmu\text{M}\) and sub-\(\upmu\text{M}\) inhibitory activity on cholinesterasees (\(\text{IC}_{50}=0.125\text{--}0.412~{}\upmu\text{M}\) for AChE and \(\text{IC}_{50}=0.245\text{--}1.283~{}\upmu\text{M}\) for BuChE) and even better activity on the PDE (\(\text{IC}_{50}=0.041\text{--}1.307~{}\upmu\text{M}\)) [10]. Other alkaloids of natural origin have also been reported as dual inhibitors targeting AChE and PDEs. In particular, natural compounds from camel artemisia (_Peganum nigelastrum_) and their synthetic derivatives were tested in this context. [PERSON] et al.