Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 366, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2022.110129
Keywords
Trypanosoma cruzi; Neolignans; Plasma membrane; Mitochondrial membrane
Funding
- CAPES-COFECUB [PHC 884-17, 883/2017, 404843/2018-2]
- CNPq [88887.198050/2018-00, 312288/2019-0]
- FAPESP [2021/02789-7, 2021/04464-8, 2018/01258-5, 2018/07885-1, 2018/10279-6, 2017/24931- 4, 2017/17044-1, 2016/05006-5]
- CAPES [001]
- Institutional Internationalization Program CAPES-PrInt/UFABC
- CNPq
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In this study, compounds isolated from N. leucantha were used as starting material to synthesize two new derivatives, which showed activity against trypanosome and no toxicity to mammalian cells. Mechanism study revealed that the derivatives caused depolarization of the parasite's plasma membrane and collapse of mitochondrial membrane potential. Therefore, this compound could be a potential candidate for future drug design in the treatment of Chagas disease.
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 mu M, respectively) and against intracellular amastigotes (EC50 values of 10.2 and 6.1 mu M, respectively). Additionally, compound 2a demonstrated no mammalian cytotoxicity up to 200 mu M whereas compound 1a exhibited a CC50 value of 139.8 mu M. 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.
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