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

Author(s)

Levatti, Erica V. de Castro ; Costa-Silva, Thais A. ; Morais, Thiago R. ; Fernandes, Joao Paulo S. ; Lago, Joao Henrique G. ; Tempone, Andre G.

• Document type: Journal article
• Source: Biochimie; v. 208, p. 10-pg., 2023-05-22.

Abstract

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), Oallyl (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 mM, respectively. Despite no induction of hemolytic activity, only compound 1b resulted in mammalian cytotoxicity (CC50 1/4 64 mM). 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. (c) 2023 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. (AU)

• FAPESP's process: 21/02789-7 - Search for bioactive metabolites with antiparasitic action in plant species from Atlantic Forest and Cerrado regions - a chemical, phenotypical, and metabolomic approach
• Grantee: João Henrique Ghilardi Lago
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
• FAPESP's process: 21/04464-8 - Microbial and plant prototypes as drug candidates for protozoan neglected diseases and multidrug-resistant bacteria
• Grantee: André Gustavo Tempone Cardoso
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/50333-7 - Institutional research development plan of the Instituto Adolfo Lutz (PDIp)
• Grantee: Carlos Henrique Camargo
• Support Opportunities: Research Grants - State Research Institutes Modernization Program