Chemically engineered essential oils prepared through thiocyanation under solvent-free conditions: chemical and bioactivity alteration

Abstract

The generation of chemically engineered essential oils (CEEOs) prepared from bi-heteroatomic reactions using ammonium thiocyanate as a source of bioactive compounds is described. The impact of the reaction on the chemical composition of the mixtures was qualitatively demonstrated through GC-MS, utilizing univariate and multivariate analysis. The reaction transformed most of the components in the natural mixtures, thereby expanding the chemical diversity of the mixtures. Changes in inhibition properties between natural and CEEOs were demonstrated through acetylcholinesterase TLC autography, resulting in a threefold increase in the number of positive events due to the modification process. The chemically engineered Origanum vulgare L. essential oil was subjected to bioguided fractionation, leading to the discovery of four new active compounds with similar or higher potency than eserine against the enzyme. The results suggest that the directed chemical transformation of essential oils can be a valuable strategy for discovering new acetylcholinesterase (AChE) inhibitors.

Keywords: Acetylcholinesterase inhibitors; Ammonium thiocyanate; Bioactive compounds; Chemically modified essential oils; Iodine catalysis.

Fig. 1

Box and whiskers plot for a number of peaks from EOs with DA and MH (red and blue respectively) and CEEOs with DA and MH (green and black respectively) detected in the GC–MS chromatograms, b percentage of peaks that disappeared with DA and MH (red and blue respectively) and that appeared with DA and MH (green and black respectively) and c Score plot of PCA of GC–MS data for EOs (green X) and CEEOs (blue circles). The mean value is represented with a +

Fig. 2

Changes observed in AChE inhibition by the reaction over EOs. a Green bars illustrate de biological activity in EOs and pink bars indicate the biological activity present in the CEEOs

Fig. 3

TLC of OV a EO revealed with AChE assay, b CEEO revealed with AChE assay and c CEEO revealed with false-positive AChE assay. Mobile phase hexane: ethyl acetate (75:25)

Scheme 1

Synthesis of 5-isopropyl-2-methyl-4-thiocyanatophenol (1), 4,4′-thiobis(5-isopropyl-2-methylphenol) (2), 4-((5-(4-hydroxy-2-isopropyl-5-methylphenyl)-1,2,4-thiadiazol-3-yl)thio)-5-isopropyl-2-methylphenol (3), and 4,4′-((1,2,4-thiadiazole-3,5-diyl)bis(sulfanediyl))bis(5-isopropyl-2-methylphenol) (4)

Scheme 2

Proposed mechanism for a 4,4′-thiobis(5-isopropyl-2-methylphenol) (2), b 4-((5-(4-hydroxy-2-isopropyl-5-methylphenyl)-1,2,4-thiadiazol-3-yl)thio)-5-isopropyl-2-methylphenol (3), and c 4,4′-((1,2,4-thiadiazole-3,5-diyl)bis(sulfanediyl))bis(5-isopropyl-2-methylphenol) (4)