Toward New Therapeutics for Visceral Leishmaniasis: Efficacy and Mechanism of Action of Amides Inspired by Gibbilimbol B.

Autor: Baltazar FN; Pathophysiology Laboratory, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900 São Paulo, São Paulo, Brazil., Amaral M; Pathophysiology Laboratory, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900 São Paulo, São Paulo, Brazil., Romanelli MM; Pathophysiology Laboratory, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900 São Paulo, São Paulo, Brazil., de Castro Levatti EV; Pathophysiology Laboratory, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900 São Paulo, São Paulo, Brazil., Ramos FF; Pathophysiology Laboratory, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900 São Paulo, São Paulo, Brazil.; Department of Pharmaceutical Sciences, Federal University of São Paulo, Rua São Nicolau, 210, 09913030 Diadema, São Paulo, Brazil., Paulo Melchior de Oliveira Leão L; Institute of Chemistry, Federal University of Alfenas (UNIFAL), R. Gabriel Monteiro da Silva, 700, 37130-000 Alfenas, Minas Gerais, Brazil., Chagas-Paula DA; Institute of Chemistry, Federal University of Alfenas (UNIFAL), R. Gabriel Monteiro da Silva, 700, 37130-000 Alfenas, Minas Gerais, Brazil., Soares MG; Institute of Chemistry, Federal University of Alfenas (UNIFAL), R. Gabriel Monteiro da Silva, 700, 37130-000 Alfenas, Minas Gerais, Brazil., Dias DF; Institute of Chemistry, Federal University of Alfenas (UNIFAL), R. Gabriel Monteiro da Silva, 700, 37130-000 Alfenas, Minas Gerais, Brazil., Aranha CMSQ; Department of Medicine, Federal University of São Paulo (UNIFESP), Av. Dr. Arnaldo, 455, 01246-903 São Paulo, São Paulo, Brazil., Dos Santos Fernandes JP; Department of Pharmaceutical Sciences, Federal University of São Paulo, Rua São Nicolau, 210, 09913030 Diadema, São Paulo, Brazil., Lago JHG; Centre of Natural Sciences and Humanities, Universidade Federal do ABC, Av. dos Estados, 5001, 09210-580 Santo André, São Paulo, Brazil., Tempone AG; Pathophysiology Laboratory, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900 São Paulo, São Paulo, Brazil.
Jazyk: angličtina
Zdroj: ACS omega [ACS Omega] 2024 Oct 08; Vol. 9 (44), pp. 44385-44395. Date of Electronic Publication: 2024 Oct 08 (Print Publication: 2024).
DOI: 10.1021/acsomega.4c05510
Abstrakt: The problems with current strategies to control canine visceral Leishmaniasis (CVL), which include the euthanasia of infected animals, and also the toxicity of the drugs currently used in human treatments for CVL, add urgency to the search for new therapeutic agents. This study aimed to evaluate the activity against Leishmania (L.) infantum of 12 amides that are chemically inspired by gibbilimbol B, a bioactive natural product that was initially obtained from Piper malacophyllum . Three of these compounds- N -(2-ethylhexyl)-4-chlorobenzamide ( 9 ), N -(2-ethylhexyl)-4-nitrobenzamide ( 10 ), and N -(2-ethylhexyl)-4-( tert -butyl)benzamide ( 12 ) -demonstrated activity against the intracellular amastigotes without toxicity to mammalian host cells (CC 50 > 200 μM); compounds 9 , 10 , and 12 resulted in EC 50 values of 12.7, 12.2, and 5.1 μM, respectively. In silico drug-likeness studies predicted that these compounds would show high levels of gastrointestinal absorption, would be able to penetrate the blood-brain barrier, would show moderate solubility, and would not show unwanted molecular interactions. Due to their promising pharmacological profiles, compounds 9 and 10 were selected for mechanism of action studies (MoA). The MoA studies in L. (L.) infantum revealed that neither of the compounds affected the permeabilization of the plasma membrane. Nevertheless, compound 9 induced strong alkalinization of acidocalcisomes, which resulted in a significant and rapid increase in intracellular Ca 2+ levels, thereby causing the depolarization of the mitochondrial membrane potential and a reduction in the levels of reactive oxygen species (ROS). In contrast, compound 10 induced a gradual increase in intracellular Ca 2+ levels and a similarly gradual reduction in ROS levels, but it caused neither acidocalcisome alkalinization nor mitochondrial membrane potential depolarization. Finally, the MALDI-TOF/MS assessment of protein alterations in L. (L.) infantum treated separately with compounds 9 and 10 revealed changes in mass spectral profiles from both treatments. These results highlight the anti- L. (L.) infantum potential of these amides-especially for compounds 9 and 10 -and they suggest that these compounds could be promising candidates for future in vivo studies in VL-models.
Competing Interests: The authors declare no competing financial interest.
(© 2024 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE
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