Antitrypanosomal activity and evaluation of the structure-activity relationship of diterpenes from aerial parts of Baccharis retusa (Asteraceae) and related semi-synthetic derivatives

Chagas disease belongs to the group of Neglected Tropical Diseases (NTD) and its etiologic agent is the protozoan Trypanosoma cruzi. This disease is spread worldwide, especially in Latin America, and it is estimated that about 6-7 million people are infected all over the world [1]. Due to the lack of drugs available for the treatment of this disease, natural products are an important source for the development of new bioactive prototypes. In this context, the hexane extract from aerial parts of Baccharis retusa afforded two bioactive diterpenes, ent-kaurenoic acid and 15β-senecioyloxy-ent-kaurenoic acid (1), this last natural product exhibiting CE50 of 3.8 M against trypomastigote forms of T. cruzi but inactive against intracellular forms (amastigotes) of this parasite [2]. In continuation of this work, the preparation of five semisynthetic derivatives (1a-e), involving esterification and/or reduction of double bonds (carbonyl and olefinic carbons) of compound 1. All prepared compounds were characterized by analysis of NMR and MS spectra and their potential was evaluated against amastigote forms of T. cruzi and NCTC cells.
Among tested derivatives, compound 1d displayed an EC50 of 11.8 µM which is lower than the standard drug benznidazole (EC50 of 16.2 µM) and exhibited reduced toxicity (CC50 > 200 µM) with SI > 12. The related derivative 1e was inactive (EC50 > 200 µM), indicating that the presence of double bond at C-2’, in order to form a conjugated system, is crucial to activity. Compound 1a was also inactive (EC50 > 200 µM) while compound 1b displayed moderate activity (CE50 = 20.1 µM) suggesting that the presence of senecioyloxy group at C-15 plays an important role in the antitrypanosomal activity. On the other hand, compound 1c exhibited high activity (EC50 = 13.8 M) but expressive toxicity (CC50 = 108 µM) and, therefore, an SI = 8. Based on the obtained data, this study afforded a semi-synthetic derivative (1d) which could be easily prepared from inactive natural product 1 isolated in large amount from aerial parts of B. retusa.