Synthesis and Activity Evaluation of Vinpocetine-Derived Indole Alkaloids

Abstract

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.

Keywords: PDE1A; biological evaluation; molecular docking; structural modification; vinpocetine.

Figure 1

The design route of vinpocetine derivatives.

Figure 2

Synthetic route of vinpocetine derivatives 1–25. Reagents and conditions: a. LiAlH₄, dry THF, rt; b. Halogenated hydrocarbon, NaH (60%), dry THF, rt.

Figure 3

Predicted binding of compounds 4 (a) and 25 (b) to PDE1A.