Lethal action of Licarin A derivatives in Leishmania (L.) infantum: Imbalance of calcium and bioenergetic metabolism.

Autor: de Castro Levatti EV; Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, 01246-000, Brazil., Costa-Silva TA; Centre of Natural Sciences and Humanities, Universidade Federal do ABC, São Paulo, 09210-580, Brazil., Morais TR; Centre of Natural Sciences and Humanities, Universidade Federal do ABC, São Paulo, 09210-580, Brazil., Fernandes JPS; Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, 09972-270, Brazil., Lago JHG; Centre of Natural Sciences and Humanities, Universidade Federal do ABC, São Paulo, 09210-580, Brazil. Electronic address: joao.lago@ufabc.edu.br., Tempone AG; Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, 01246-000, Brazil. Electronic address: andre.tempone@ial.sp.gov.br.
Jazyk: angličtina
Zdroj: Biochimie [Biochimie] 2023 May; Vol. 208, pp. 141-150. Date of Electronic Publication: 2022 Dec 29.
DOI: 10.1016/j.biochi.2022.12.018
Abstrakt: Natural metabolites present an extraordinary chemo-diversity and have been used as the inspiration for new drugs. Considering the need for new treatments against the neglected parasitic disease leishmaniasis, three semi-synthetic derivatives of natural neolignane licarin A were prepared: O-acetyl (1a), O-allyl (1b), and 5-allyl (1c). Using an ex vivo assay, compounds 1a, 1b, and 1c showed activity against the intracellular amastigotes of Leishmania (L.) infantum, with IC 50 values of 9, 13, and 10 μM, respectively. Despite no induction of hemolytic activity, only compound 1b resulted in mammalian cytotoxicity (CC 50  = 64 μM). The most potent compounds (1a and 1c) resulted in selectivity indexes >18. The mechanism of action of compound 1c was evaluated by fluorescent/luminescent based techniques and MALDI-TOF/MS. After a short incubation period, increased levels of the cytosolic calcium were observed in the parasites, with alkalinization of the acidocalcisomes. Compound 1c also induced mitochondrial hyperpolarization, resulting in decreased levels of ATP without altering the reactive oxygen species (ROS). Neither plasma membrane damages nor DNA fragmentation were observed after the treatment, but a reduction in the cellular proliferation was detected. Using MALDI-TOF/MS, mass spectral alterations of promastigote proteins were observed when compared to untreated and miltefosine-treated groups. This chemically modified neolignan induced lethal alterations of the bioenergetic and protein metabolism of Leishmania. Future PKPD and animal efficacy studies are needed to optimize this promising natural-derived compound.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest, financial or otherwise.
(Copyright © 2023 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
Databáze: MEDLINE
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