Synthesis and Molecular Modeling of Antioxidant and Anti-Inflammatory Five-Membered Heterocycle-Cinnamic Acid Hybrids

Abstract

In this study, the design and synthesis of a novel series of cinnamic acid and 1,2,4-triazole hybrids were reported, aiming to enhance antioxidant and lipoxygenase inhibitory activities through pharmacophore combination. Cinnamic acid derivatives and 1,2,4-triazoles exhibit a broad spectrum of biological activities; therefore, by synthesizing hybrid molecules, we would like to exploit the beneficial characteristics of each scaffold. The general synthetic procedure comprises three synthetic steps, starting from the reaction of appropriate substituted cinnamic acid with hydrazine monohydrate in acetonitrile with cyclohexane and resulting in the formation of hydrazides. Consequently, the hydrazides reacted with phenylisothiocyanate under microwave irradiation conditions. Then, cyclization proceeded to the 1,2,4-triazole after the addition of NaOH solution and microwave irradiation. All the synthesized derivatives have been studied for their ability (a) to interact with the free radical DPPH, (b) inhibit lipid peroxidation induced by AAPH, and (c) inhibit soybean lipoxygenase. The synthesized derivatives have shown significant antioxidant activity and have been proved to be very good lipoxygenase inhibitors. Compounds 4b and 4g (IC₅₀ = 4.5 μM) are the most potent within the series followed by compound 6a (IC₅₀ = 5.0 μM). All the synthesized derivatives have been subjected to docking studies related to soybean lipoxygenase. Compound 4g exhibited a docking score of -9.2 kcal/mol and formed hydrophobic interactions with Val126, Tyr525, Lys526, Arg533, and Trp772, as well as a π-cation interaction with Lys526.

Keywords: 1,2,4-triazole; 1,3,4-oxadiazole; anti-inflammatory; antioxidant; chimeric molecules; cinnamic acid derivatives.

Scheme 1

Structures of triazole and oxadiazole derivatives exhibiting potential anti-inflammatory activity (I–VIII) [2,3,4,6,7,9].

Scheme 2

Chemical structures of bioactive cinnamic acid derivatives [14,15,16,17,18,19,20,21].

Figure 1

Overview of the inflammatory pathway activated by infection or tissue damage.

Figure 2

Free radicals induce oxidative damage to membrane lipids and proteins, leading to cellular component injury.

Scheme 3

Representative five-membered heterocyclic scaffolds studied for their antioxidant and anti-inflammatory activities.

Figure 3

Hybrid molecules showing key pharmacophores, including cinnamic acid, 1,2,4-triazole, and 1,3,4-oxadiazole moieties.

Scheme 4

Synthesis of the key intermediates (1a–g), (2a–g), and (3a–g).

Scheme 5

Synthesis of the target molecules 4a–g, 5a–c, and 6a.

Figure 4

The 3D preferred docking pose of compound 4g (depicted in cyan) bound to soybean lipoxygenase. Iron appears as an orange sphere.

Figure 5

The 3D preferred docking pose of compound 6a (depicted in magenta) bound to soybean lipoxygenase. The one hydrogen bond is illustrated with dashed gray lines. Iron appears as an orange sphere.

Figure 6

Ligand interaction diagram of compound 4g to soybean lipoxygenase (ID: 3PZW). The π−cation interaction is presented with a red line. The hydrophobic residues are shown in green, the polar ones in cyan, and the positive charged in blue. The figure is made with free Maestro [67]. (Free Maestro academic license—Schrödinger Release 2025-2: Maestro, Schrödinger, LLC, New York, NY, USA, 2025).

Figure 7

Ligand interaction diagram of compound 6a to soybean lipoxygenase (ID: 3PZW). The hydrogen bond interaction with residues is illustrated by a purple dashed arrow and the π−cation interaction is presented with a red line. The hydrophobic residues are shown in green, the polar ones in cyan, the positive charged in blue, and the negative charged in red. The figure is made with free Maestro [67]. (Free Maestro academic license—Schrödinger Release 2025-2: Maestro, Schrödinger, LLC, New York, NY, USA, 2025).