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. (1st October 2022)

• Record Type: Journal Article
• Authors: Galhardo, Thalita S.; Ueno, Anderson K.; Costa-Silva, Thaís A.; Tempone, André G.; Carvalho, Wagner A.; Fischmeister, Cedric; Bruneau, Christian; Mandelli, Dalmo; Lago, João Henrique G.
• Is Part Of: Chemico-biological interactions. Volume 366(2022)
• Publication Date: 2022-10-01
• Subjects: Trypanosoma cruzi -- Neolignans -- Plasma membrane -- Mitochondrial membrane; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2022.110129
• Languages: English
• ISSNs: 0009-2797

Abstract

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. Highlights: Two new derivatives from dehydrodieugenol B were prepared using olefin cross-metathesis. Prepared compounds displayed activity against Trypanosoma cruzi. Prepared compounds demonstrated effects in plasma and mitochondrial membranes.