Topical Anti-inflammatory Activity of New Hybrid Molecules of Terpenes and Synthetic Drugs.

Cristina Theoduloz,Mariano Pertino,Fernanda Bustamante,Gabriela Valenzuela-Barra,Carla Delporte,Guillermo Schmeda-Hirschmann,Solange Cádiz,Ximena Silva

doi:10.3390/molecules200611219

Cristina Theoduloz, Mariano Pertino + Show 6 more

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https://doi.org/10.3390/molecules200611219

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Abstract

The aim of the study was to assess changes in the activity of anti-inflammatory terpenes from Chilean medicinal plants after the formation of derivatives incorporating synthetic anti-inflammatory agents. Ten new hybrid molecules were synthesized combining terpenes (ferruginol (1), imbricatolic acid (2) and oleanolic acid (3)) with ibuprofen (4) or naproxen (5). The topical anti-inflammatory activity of the compounds was assessed in mice by the arachidonic acid (AA) and 12-O-tetradecanoyl phorbol 13-acetate (TPA) induced ear edema assays. Basal cytotoxicity was determined towards human lung fibroblasts, gastric epithelial cells and hepatocytes. At 1.4 µmol/mouse, a strong anti-inflammatory effect in the TPA assay was observed for oleanoyl ibuprofenate 12 (79.9%) and oleanoyl ibuprofenate methyl ester 15 (80.0%). In the AA assay, the best activity was observed for 12 at 3.2 µmol/mouse, with 56.8% reduction of inflammation, in the same range as nimesulide (48.9%). All the terpenyl-synthetic anti-inflammatory hybrids showed better effects in the TPA assay, with best activity for 6, 12 and 15. The cytotoxicity of the compounds 8 and 10 with a free COOH, was higher than that of 2. The derivatives from 3 were less toxic than the triterpene. Several of the new compounds presented better anti-inflammatory effect and lower cytotoxicity than the parent terpenes.

Highlights

Traditional medicine in South America has a vast knowledge in the use of plants to maintain and restore health
The aim of the study was to disclose possible changes in the topical anti-inflammatory effect and cytotoxicity of terpenes obtained from some Chilean crude drugs when combined with synthetic anti-inflammatory compounds
The comparative topical anti-inflammatory effect of the compounds 1–15 was assessed in the model of ear edema induction in mice, using tetradecanoyl phorbol 13-acetate (TPA) and arachidonic acid (AA)

Summary

Introduction

Traditional medicine in South America has a vast knowledge in the use of plants to maintain and restore health. Diterpenes and triterpenes are natural products with potential as anti-inflammatory agents. Labdane diterpenes derivatives showed anti-inflammatory activity in the ear edema assay in mice as well as in macrophages [3]. Et Endl.) shows anti-inflammatory activity [5]. It presents strong inhibition of lipid peroxidation in erythrocytes [6] as well as on superoxide anion generated in phorbol myristate acetate-stimulated rat neutrophils [7]. The triterpene oleanolic acid has been shown to display several relevant biological activities, including the modulation of the immune-inflammatory response [8], reduction of differentiation markers in adipocytes and suppression of inflammation associated with obesity [9]. Pentacyclic triterpene acids from Ugni molinae leaves presented topical anti-inflammatory effect in mice [11]

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