Given that flavonoids as a family of naturally occurring polyphenols have antioxidant, 27 antiviral, anticancer, and antimicrobial activities, we chose the flavonoid framework for our molecular design of small molecules with reactivities of multiple pathological targets. As presented in Fig. , some structural moieties of flavonoids are reported to be important for modulating free radicals, AChE, metal-free Ab, and metal-Ab: (i) The unsaturated bond between C2 and C3 on the C ring of flavonoids could interact with the hydrophobic self-recognition (Leu17-Ala21) and C-terminal regions of Ab that are essential for its aggregation process; (ii) the 4-oxo functionality on the C ring as an oxygen (O) donor atom can participate in metal coordination; (iii) the chromone moiety (A and C rings) is responsible for the reactivity of flavonoids against AChE through the interactions with amino acid residues containing an aromatic ring at their side chains (e.g., Trp86, Phe295, and Tyr341) within the hydrophobic binding pocket of AChE; 36 (iv) both the number and position of hydroxyl groups are associated with redox properties of flavonoids. In addition to the abovementioned structural features of flavonoids, the incorporation of hydroxyl groups on the B and C rings and the isoflavone variation to regulate pathological factors have been recently identified; however, the information on structural and chemical properties on the A ring for multiple reactivities towards our desired targets, except for AChE, 39 is very limited. Thus, to gain a full spectrum of the structure-activity relationship with respect to all the A, B, and C rings, we rationally selected a series of six flavonoids (1-6; Fig. ) through the structural variation of hydroxyl groups on the A ring that can alter their electronic and AChE-/Abinteracting properties. Compounds 1-3 containing two hydroxyl groups located at distinct positions on the A ring were first chosen. Our series also included 4 possessing three hydroxyl groups on the A ring. Compound 5 that embodies three hydroxyl groups with an electronwithdrawing chloro group at the C8 position on the A ring was additionally selected, along with 6 as a regioisomer of 4 with an isoflavone moiety. Compounds 1-6 were obtained from commercially available sources (1-4) or prepared by previously reported synthetic routes (5 40 and 6 ). The characterization of 5 and 6 was summarized in Figs. and, respectively.