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

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 (1...

Full description

Saved in:
Bibliographic Details
Published in:Biochimie 2023-05, Vol.208, p.141-150
Main Authors: de Castro Levatti, Erica V., Costa-Silva, Thais A., Morais, Thiago R., Fernandes, João Paulo S., Lago, João Henrique G., Tempone, Andre G.
Format: Article
Language:English
Subjects:
Animals
Antiprotozoal Agents - pharmacology
Calcium - metabolism
Drugs
Energy Metabolism
Leishmania infantum - metabolism
Leishmaniasis
Licarin a
Mammals - metabolism
Mechanism of action
Mice
Mice, Inbred BALB C
Mitochondria
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 IC50 values of 9, 13, and 10 μM, respectively. Despite no induction of hemolytic activity, only compound 1b resulted in mammalian cytotoxicity (CC50 = 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. •Licarin A derivatives presents a potent anti-L. (L.) infantum activity.•Compound 1c increases calcium levels and alkalinize the acidocalcisomes.•Compound 1c induces hyperpolarization of parasite mitochondria.•Compound 1c promotes protein mass spectrum alterations.•Licarin A derivatives are promising hit compounds for leishmaniasis.
ISSN:0300-9084
1638-6183
DOI:10.1016/j.biochi.2022.12.018