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This study focuses on the synthesis of novel vinpocetine derivatives (2–25) and their biological evaluation. The chemical structures of the synthesized compounds were fully characterized using techniques such as 1H NMR, 13C NMR, and HRMS. The inhibitory activity of the synthesized compounds on PDE1A was evaluated, and the results revealed that compounds 3, 4, 5, 12, 14, 21, and 25 exhibited superior inhibitory activity compared to vinpocetine. Compound 4, with a para-methylphenyl substitution, showed a 5-fold improvement in inhibitory activity with an IC50 value of 3.53 ± 0.25 μM. Additionally, compound 25, with 3-chlorothiazole substitution, displayed an 8-fold increase in inhibitory activity compared to vinpocetine (IC50 = 2.08 ± 0.16 μM). Molecular docking studies were conducted to understand the binding models of compounds 4 and 25 within the active site of PDE1A. The molecular docking study revealed additional binding interactions, such as π–π stacking and hydrogen bonding, contributing to the enhanced inhibitory activity and stability of the ligand–protein complexes. Overall, the synthesized vinpocetine derivatives demonstrated promising inhibitory activity on PDE1A, and the molecular docking studies provided insights into their binding modes, supporting further development of these compounds as potential candidates for drug research and development.

Scutellaria barbata D. Don (SB, Chinese: Ban Zhi Lian), a well-known medicinal plant used in traditional Chinese medicine, is rich in flavonoids. It possesses antitumor, anti-inflammatory, and antiviral activities. In this study, we evaluated the inhibitory activities of SB extracts and its active components against HIV-1 protease (HIV-1 PR) and SARS-CoV2 viral cathepsin L protease (Cat L PR). UPLC/HRMS was used to identify and quantify the major active flavonoids in different SB extracts, and fluorescence resonance energy transfer (FRET) assays were used to determine HIV-1 PR and Cat L PR inhibitions and identify structure–activity relationships. Molecular docking was also performed, to explore the diversification in bonding patterns of the active flavonoids upon binding to the two PRs. Three SB extracts (SBW, SB30, and SB60) and nine flavonoids inhibited HIV-1 PR with an IC50 range from 0.006 to 0.83 mg/mL. Six of the flavonoids showed 10~37.6% inhibition of Cat L PR at a concentration of 0.1 mg/mL. The results showed that the introduction of the 4′-hydroxyl and 6-hydroxyl/methoxy groups was essential in the 5,6,7-trihydroxyl and 5,7,4′-trihydroxyl flavones, respectively, to enhance their dual anti-PR activities. Hence, the 5,6,7,4′-tetrahydroxyl flavone scutellarein (HIV-1 PR, IC50 = 0.068 mg/mL; Cat L PR, IC50 = 0.43 mg/mL) may serve as a lead compound to develop more effective dual protease inhibitors. The 5,7,3′,4′-tetrahydroxyl flavone luteolin also showed a potent and selective inhibition of HIV-1 PR (IC50 = 0.039 mg/mL).