New derivatives from dehydrodieugenol B and its methyl ether displayed high anti-Trypanosoma cruzi activity and cause depolarization of the plasma membrane and collapse the mitochondrial membrane potential

Abstract

In the present work, dehydrodieugenol B (1) and its methyl ether (2), isolated from Nectandra leucantha twigs, were used as starting material for the preparation of two new derivatives (1a and 2a) containing an additional methoxycarbonyl unit on allyl side chains. Compounds 1a and 2a demonstrated activity against trypomastigotes (EC₅₀ values of 13.5 and 23.0 μM, respectively) and against intracellular amastigotes (EC₅₀ values of 10.2 and 6.1 μM, respectively). Additionally, compound 2a demonstrated no mammalian cytotoxicity up to 200 μM whereas compound 1a exhibited a CC₅₀ value of 139.8 μM. The mechanism of action studies of compounds 1a and 2a demonstrated a significant depolarization of the plasma membrane potential in trypomastigotes, followed by a mitochondrial membrane potential collapse. Neither calcium level nor reactive oxygen species alterations were observed after a short-time incubation. Considering the potential of compound 2a against T. cruzi and its simple preparation from the natural product 2, isolated from N. leucantha, this compound could be considered a new hit for future drug design studies in Chagas disease.

Keywords: Mitochondrial membrane; Neolignans; Plasma membrane; Trypanosoma cruzi.