Ferulic, Sinapic, 3,4-Dimethoxycinnamic Acid and Indomethacin Derivatives with Antioxidant, Anti-Inflammatory and Hypolipidemic Functionality

Abstract

A series of thiomorpholine and cinnamyl alcohol derivatives, conjugated with cinnamic acid-containing moieties, such as ferulic acid, sinapic acid and 3,4-dimethoxycinnamic acid, were synthesized and tested for their antioxidant, anti-inflammatory and hypolipidemic properties. An indomethacin ester with 2,6-di-tert-butyl-4-(hydroxymethyl)phenol was also prepared for reasons of comparison. The majority of the compounds demonstrated considerable antioxidant capacity and radical scavenging activity, reaching up to levels similar to the well-known antioxidant trolox. Some of them had an increased anti-inflammatory effect on the reduction of carrageenan-induced rat paw edema (range 17-72% at 150 μmol/kg), having comparable activity to the NSAIDs (non-steroidal anti-inflammatory drugs) used as reference. They had moderate activity in soybean lipoxygenase inhibition. All the tested compounds exhibited a significant decrease in lipidemic indices in Triton-induced hyperlipidemia in rats, whilst the most active triglycerides and total cholesterol decreased by 72.5% and 76%, respectively, at 150 μmol/kg (i.p.), slightly better than that of simvastatin, a well-known hypocholesterolemic drug, but with negligible triglyceride-lowering effect. Since our designed compounds seem to exhibit multiple pharmacological activities, they may be of use in occasions involving inflammation, oxidative stress, lipidemic deregulation and degenerative conditions.

Keywords: anti-inflammatory; antioxidant activity; cinnamic acid derivatives; dyslipidemia; ferulic acid; inflammation; sinapic acid.

Figure 1

Structures of the synthesized compounds (compound 1: (E)-3-(4-hydroxy-3-methoxyphenyl)-1-thiomorpholinoprop-2-en-1-one; compound 2: (E)-cinnamyl 3-(4-hydroxy-3-methoxyphenyl)acrylate; compound 3: (E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-thiomorpholinoprop-2-en-1-one; compound 4: (E)-cinnamyl 3-(4-hydroxy-3,5-dimethoxyphenyl)acrylate; compound 5: (E)-3-(3,4-dimethoxyphenyl)-1-thiomorpholinoprop-2-en-1-one; compound 6: (E)-cinnamyl 3-(3,4-dimethoxyphenyl)acrylate; compound 7: 3,5-di-tert-butyl-4-hydroxybenzyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate).

Figure 2

Synthesis of compounds 1–7.

Figure 3

The effect of various concentrations of the active compounds 1, 2, 3, 4 and 7 on the time course of lipid peroxidation. For control groups, dimethylsulfoxide alone, instead of solution of the tested compound in dimethylsulfoxide, was used. All determinations were performed in triplicate, and the standard deviation was always within ±10% of the mean value.

Figure 4

Time course of DPPH scavenging with the active compounds 1, 3 and 7. In the control group, ethanol alone was used in the place of compounds. All determinations were performed in triplicate, and standard deviation was always within ±10% of the mean value.