Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in Trypanosoma cruzi

Author(s)

Amaral, Maiara ; Varela, Marina T. ; Kant, Ravi ; Christodoulides, Myron ; Fernandes, Joao Paulo S. ; Tempone, Andre G.

• Document type: Journal article
• Source: LIFE-BASEL; v. 13, n. 3, p. 17-pg., 2023-03-01.

Abstract

Chagas disease is an endemic tropical disease caused by the protozoan Trypanosoma cruzi, which affects around 7 million people worldwide, mostly in development countries. The treatment relies on only two available drugs, with severe adverse effects and a limited efficacy. Therefore, the search for new therapies is a legitimate need. Within this context, our group reported the anti-Trypanosoma cruzi activity of gibbilimbol B, a natural alkylphenol isolated from the plant Piper malacophyllum. Two synthetic derivatives, LINS03018 (1) and LINS03024 (2), demonstrated a higher antiparasitic potency and were selected for mechanism of action investigations. Our studies revealed no alterations in the plasma membrane potential, but a rapid alkalinization of the acidocalcisomes. Nevertheless, compound 1 exhibit a pronounced effect in the bioenergetics metabolism, with a mitochondrial impairment and consequent decrease in ATP and reactive oxygen species (ROS) levels. Compound 2 only depolarized the mitochondrial membrane potential, with no interferences in the respiratory chain. Additionally, no macrophages response of nitric oxide (NO) was observed in both compounds. Noteworthy, simple structure modifications in these derivatives induced significant differences in their lethal effects. Thus, this work reinforces the importance of the mechanism of action investigations at the early phases of drug discovery and support further developments of the series. (AU)

• 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: 18/26655-7 - Natural metabolites for treating antimicrobial resistant gonorrhoea and visceral leishmaniasis
• 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
• FAPESP's process: 18/03918-2 - Evaluation of the antiparasitic activity and cytotoxicity of natural products derivatives in Trypanosoma cruzi: design and synthesis of analogues potentially superior
• Grantee: Marina Themoteo Varela
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/24028-8 - Substituted aryl-alkylamide-piperazines as multitarget ligands: synthesis and assessment of the activity on relevant targets for the treatment of CNS disorders
• Grantee: João Paulo dos Santos Fernandes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/25128-3 - Optimization of natural scaffolds as new therapeutic candidates for Visceral Leishmaniasis
• Grantee: Maiara Amaral de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate