*5.2. Flavonols*

Quercetin is one of the main flavonoids identified in several natural sources, including Maqui [119]. Both antiplatelet potential and other biological properties have been attributed to this flavonol. Quercetin inhibits platelet aggregation induced by collagen, with an IC50 = 6 μg/mL at a concentration of 5 μg/mL of collagen [120]. The antiplatelet mechanism of this flavonoid has been related to the inhibition of collagen-stimulated tyrosine phosphorylation, a key component of the collagen signaling pathway through glycoprotein VI, Syk [121]. This compound has not only shown potent activity against collagen; previous studies report that it inhibits platelet aggregation induced by AA (substrate of cyclooxygenase-1 (COX-1)) and by U46619 (synthetic mimetic of TxA2) [122].


**Table 3.** Antiplatelet activity of anthocyanins and phenolic compounds in Maqui.



Previous works show the cardioprotective potential of quercetin and kaempferol, as well as their derivatives. Quercetin 3-*O*-[(6-*O*-E-feruloyl)-β-D-glucopyranosyl-(1→2)]-β-Dgalactopyranoside-7-*O*-β-D-glucuropyranoside) and kaempferol 3-*O*-[(6-*O*-E-caffeoyl)-β-Dglucopyranosyl-(1→2)]-β-D-galactopyranoside-7-*O*-(2-*O*-E-caffeoyl )-β-D–glucuropyranoside isolated from *Lens culinaris* Medik. showed potent antiplatelet action. Results revealed decreased collagen adhesion of resting platelets and thrombin-activated platelets after incubation with quercetin and kaempferol derivatives [105]. On the other hand, kaempferol has shown its potential to reduce and prevent thrombosis. The background shows that this flavonoid inhibits fibrin polymer formation, attenuates phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38, c-Jun N-terminal kinase (JNK)1/2, and phosphoinositide 3-kinase (PI3K)/PKB (AKT) in thrombin-stimulated cells and decreases collagen/epinephrine-stimulated platelet aggregation by 34.6%. Additionally, kaempferol protected mice from thrombosis in models of acute thromboembolism induced by collagen/epinephrine and thrombin, as well as carotid artery thrombus induced by FeCl3 [104]. Another flavonol that has been identified in Maqui and that stands out for its antiplatelet action is myricetin. This compound reduces the ability of platelets to spread over collagen and form thrombi in vitro. This effect has been attributed mainly to the inhibition of PDI and ERp5 by binding to myricetin, forming non-covalent bonds [107]. Additionally, myricetin has been shown at physiologically relevant concentrations to inhibit platelet aggregation induced by TRAP-6 and AA. It also inhibits fibrinogen binding and collagen-related peptide-induced alpha granule secretion [123]. The inhibitory effect against several platelet agonists suggests that this flavonoid can act on molecules common to different pathways [107,123].

Isorhamnetin was one of the compounds that presented a positive correlation between its concentration and the antiplatelet activity of Maqui extracts [93]. The effect of isorhamnetin on mitochondrial function, platelet adhesion, and thrombus formation was evaluated under conditions of controlled blood flow in the Badimon perfusion chamber. This flavonol showed antiplatelet activity induced by collagen, and thrombin receptor activator peptide-6 (TRAP-6), with IC50 values of 8.1 ± 2.6 μM and 16.1 ± 11.1 μM, respectively [124]. It also decreased the mitochondrial membrane potential and reduced platelet deposition on the thrombus, confirming its antithrombotic effect [124].

Isorhamnetin and tamarixetine, quercetin methylated metabolites, stand out for their antiplatelet potential, even showing better results than aspirin in an aggregometry test. These compounds inhibit human platelet aggregation and suppress activating processes, including granule secretion, αIIbβ3 integrin function, calcium mobilization, and spleen tyrosine kinase (Syk). They also attenuated thrombus formation in an in vitro microfluidic model, while isorhamnetin inhibited thrombosis in a mouse model of laser injury [125].

### *5.3. Flavones*

Eriodictyol, a flavone present in Maqui, inhibits platelet aggregation stimulated by collagen and AA, in platelet-rich plasma (IC50 = 912.9 ± 37 μM and IC50 = 1027.3 ± 551 μM, respectively) [110]. On the other hand, hesperetin can selectively inhibit collagen- and AA-mediated signal transduction, with IC50 of 20.5 ± 3.5 and 69.2 ± 5.1 μM, respectively. The proposed mechanism suggests the inhibition of PLC-γ2 phosphorylation and the activity of COX-1 [111].
