## 2 Multi-Target Natural and Nature-Inspired Compounds
### Natural Extracts Containing Polyphenic Acids  
Several recent reports investigated the issue of dual cholinesterase-PDE inhibition from a slightly different perspective [59, 60, 61]. Many authors, indeed, described the activity on such enzymes, and in particular on AChE and on the PDE5 isoform, of whole aqueous or ethanolic extracts of plants or plant parts. In such research works, these tests are generally paired by analytical profiling, by means of HPLC or other chromatographic techniques, providing a description of the content of the studied extracts. In this context, [PERSON] et al. reported the in vitro activity of Nigerian plantin (_Musa sapitent_) extracts. In particular, the authors prepared aqueous extracts of unripe and ripe plantain peels using distilled water. The extracts were analyzed using HPLC-DAD, showing that rutin, caffeic acid and quercetin were the most abundant components of phenolic fraction of ripe peel extract, while unripe peel extract was rich in rutin, chlorogenic acid and catechin. Unripe peel extract was found to be more efficient in inhibiting AChE (IC\({}_{50}\) = 6.30 \(\upmu\)g/mL) and PDE5 (IC\({}_{50}\) = 3.10 \(\upmu\)g/mL) isolated from rats [59]. Similarly, the same research group presented a study focused on spice extracts. In particular, alligator pepper (_Aframomum melegeta_) and basetered melegueta (_Aframomum danieli_) were considered. In this case, the authors performed the extraction of alkaloids using a 10% acetic acid solution in ethanol. The composition of such extracts was investigated by GC-FID and revealed that, among other alkaloids, alligator pepper is particularly rich in theophylline (Figure 2), lupanine and  
Figure 4: Chemical structures of quercetin, naringenin and icarisid II, representative flavonoids studied in the cited research works. ementine. On the other hand, high concentrations of ellipcine, gingerdione and senecionine were detected in basetered melegueta extracts. Interestingly, alligator pepper extract inhibited AChE more efficiently (IC\({}_{50}\) = 5.42 \(\upmu\)g/mL), while basetered melegueta extract performed better towards PDE5 (IC\({}_{50}\) = 7.24 \(\upmu\)g/mL) [62]. African walnut (_Tetracarpidium conophorum_) is another source of natural dual inhibitors. Aqueous extracts of pulverized walnuts, with and without shell, were analyzed by HPLC-DAD, showing the presence of gallic acid, caffeic acid (Figure 5) and quercetin (Figure 4) in similar concentrations. Nevertheless, overall higher concentrations of bioactive components were observed in the first extract, which was also the most efficient in inhibiting AChE (IC\({}_{50}\) = 0.87 \(\upmu\)g/mL) and PDE5 (IC\({}_{50}\) = 8.59 \(\upmu\)g/mL) [63]. Similarly, [PERSON] et al. reported that aqueous extracts of pulverized almond (_Terminalia catappa_) leaf and stem bark modulate the activity of AChE and PDE5 in the cardiac tissue of rats (100-200 mg/kg) [61]. These parts of the plant are rich in polyphenols and organic acids, such as ferulic, caffeic, comamic (Figure 5) and 2-prenylated benzoic acid, but also of catechhin and ellagic acid derivatives [64]. [PERSON] et al. characterized the leaves extract of _Ocimum gratissimum_, a perennial medicinal plant endowed with several pharmacological properties. Aqueous extracts of _O. gratissimum_ dose-dependently inhibited AChE (IC\({}_{50}\) = 43.19-44.67 \(\upmu\)g/mL) and PDE5 (IC\({}_{50}\) = 44.23-53.99 \(\upmu\)g/mL) isolated from rat. Moreover, the extracts were tested for radical scavenging activity showing an antioxidant effect [65]. The authors connected the observed biological effects with the phenolic content of the extract, that includes rutin, kaempfer, rosmarinic acid, caffeic acid and cichoric acid [65; 66]. Taken together, the observations that can be retrieved from the reports overviewed in this section confirm the potential of flavonoids and alkaloids as dual inhibitors of AChE and PDEs, since these compounds are the most represented in the considered extracts. Similarly, the role of polyphenic acids cannot be ruled out.