Prediction, Screening, Characterization, Antioxidant and Antihypoxic Effects of Multi-Component Zwitterionic Cocrystals of Dietary Flavonoids with Picolinic Acid

The objective of this study was to predict, screen, synthesize, and investigate cocrystals of poorly soluble flavonoids that are commonly found in dietary supplements with bipolar compound picolinic acid (PA). To improve the efficiency and success rate of experimental screening, two virtual tools based on hydrogen bond propensity (HBP) and modified molecular electrostatic potential (MEP) maps were used. The prediction accuracy of HBP and MEP is 58.82% and 94.11%, respectively, presenting that the MEP model is very powerful in the discovery of pharmaceutical cocrystals. Among the 12 successfully obtained cocrystals, 4 single crystals of PA with luteolin (LUT), genistein (GEN), taxifolin (TAX), dihydromyricetin (DHM) were obtained for the first time. Charged-assisted O-H···O and N-H···O hydrogen bonds appear as main hydrogen bonding synthons, and PA adopts a zwitterionic form after cocrystallization. GEN-PA, TAX-PA, and DHM-PA showed higher DPPH• radical-scavenging capacities; LUT-PA and DHM-PA showed higher ABTS+ radical-scavenging capacities; GEN-PA and DHM-PA possessed better protective effects on H9c2 cells from hypoxic injury caused by CoCl2 than corresponding pure flavonoids.