Investigation of the radical scavenging potential of vanillin-based pyrido-dipyrimidines: experimental and in silico approach

Abstract

Antioxidants have a significant contribution in the cell protection against free radicals which may induce oxidative stress, and permanently damage the cells causing different disorders such as tumors, degenerative diseases, and accelerated aging. Nowadays, a multi-functionalized heterocyclic framework plays an important role in drug development, and it is of great importance in organic synthesis and medicinal chemistry. Encouraged by the bioactivity of the pyrido-dipyrimidine scaffold and vanillin core, herein, we made an effort to thoroughly investigate the antioxidant potential of the vanillin-based pyrido-dipyrimidines A-E to reveal novel promising free radical inhibitors. The structural analysis and the antioxidant action of the investigated molecules were performed in silico by DFT calculations. Studied compounds were screened for their antioxidant capacity using in vitro ABTS and DPPH assays. All the investigated compounds showed remarkable antioxidant activity, especially derivative A exhibiting inhibition of free radicals at the IC₅₀ value (ABTS and DPPH assay 0.1 mg ml^-1 and 0.081 mg ml^-1, respectively). Compound A has higher TEAC values implying its stronger antioxidant activity compared to a trolox standard. The applied calculation method and in vitro tests confirmed that compound A has a strong potential against free radicals and may be a novel candidate for application in antioxidant therapy.

Fig. 1. Structures of investigated pyrido-dipyrimidines A–E.

Fig. 2. Investigated torsion angles (τ1, τ2, τ3, τ4 and τ5) for molecules A (a) and B (b) (upper) and their optimized geometries (down).

Fig. 3. Spin density distribution (only positive isovalues) in the corresponding radical species of the A and B molecules calculated in methanol: A–O1 radical (a); A–O2 radical (b); A diradical (c); B radical (d).

Fig. 4. The natural charge distributions in the most stable anions formed from the A and B molecules calculated in methanol: anion A–O1 (a); anion A–O2 (b); anion B (c).

Fig. 5. Total spin density distribution in the radical cations of the A (left) and B (right) molecules calculated in methanol.