4-Quinolinylhydrazone analogues kill Leishmania (Leishmania) amazonensis by inducing apoptosis and mitochondria-dependent pathway cell death.

Autor: Granato JDT; Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil., Silva ETD; Fundação Oswaldo Cruz (Fiocruz), Instituto de Tecnologia em Fármacos Farmanguinhos, Rio de Janeiro, Brazil., Lemos ASO; Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil., Machado PA; Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil., Midlej VDV; Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil., Antinarelli LMR; Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil., Silva Neto AFD; Departamento de Medicina Veterinária, Faculdade de Medicina, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil., Souza MVN; Fundação Oswaldo Cruz (Fiocruz), Instituto de Tecnologia em Fármacos Farmanguinhos, Rio de Janeiro, Brazil., Coimbra ES; Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil.
Jazyk: angličtina
Zdroj: Chemical biology & drug design [Chem Biol Drug Des] 2024 May; Vol. 103 (5), pp. e14535.
DOI: 10.1111/cbdd.14535
Abstrakt: Despite efforts, available alternatives for the treatment of leishmaniasis are still scarce. In this work we tested a class of 15 quinolinylhydrazone analogues and presented data that support the use of the most active compound in cutaneous leishmaniasis caused by Leishmania amazonensis. In general, the compounds showed activity at low concentrations for both parasitic forms (5.33-37.04 μM to promastigotes, and 14.31-61.98 μM to amastigotes). In addition, the best compound (MHZ15) is highly selective for the parasite. Biochemical studies indicate that the treatment of promastigotes with MHZ15 leads the loss of mitochondrial potential and increase in ROS levels as the primary effects, which triggers accumulation of lipid droplets, loss of plasma membrane integrity and apoptosis hallmarks, including DNA fragmentation and phosphatidylserine exposure. These effects were similar in the intracellular form of the parasite. However, in this parasitic form there is no change in plasma membrane integrity in the observed treatment time, which can be attributed to metabolic differences and the resilience of the amastigote. Also, ultrastructural changes such as vacuolization suggesting autophagy were observed. The in vivo effectiveness of MHZ15 in the experimental model of cutaneous leishmaniasis was carried out in mice of the BALB/c strain infected with L. amazonensis. The treatment by intralesional route showed that MHZ15 acted with great efficiency with significantly reduction in the parasite load in the injured paws and draining lymph nodes, without clinical signs of distress or compromise of animal welfare. In vivo toxicity was also evaluated and null alterations in the levels of hepatic enzymes aspartate aminotransferase, and alanine aminotransferase was observed. The data presented herein demonstrates that MHZ15 exhibits a range of favorable characteristics conducive to the development of an antileishmanial agent.
(© 2024 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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