C5 induces different cell death pathways in promastigotes of Leishmania amazonensis

Abstract

Leishmaniasis is a neglected infection that is caused by Leishmania protozoa, affecting millions of people worldwide, mainly in tropical and subtropical regions. This disease has different clinical forms: cutaneous, mucocutaneous, and visceral. The drugs that are currently available for the treatment of this infection have limitations, such as high toxicity, long-term treatment, and leads to drug-resistant strains. Numerous studies, in various experimental models, have sought to develop more effective and less toxic chemotherapeutic agents against leishmaniasis. In the present study, we evaluated the mechanism of cell death that is induced by n-benzyl 1-(4-methoxy)phenyl-9H-β-carboline-3-carboxamide (C5) against Leishmania amazonensis. C5 increased reactive oxygen species production, depolarization of the mitochondrial membrane, DNA fragmentation, decrease of cell volume, lipoperoxidation, the accumulation of lipid bodies, and acidic vesicular organelles (AVOs) and caused the intense formation of autophagic compartments in L. amazonensis promastigotes. The results indicate that C5 causes L. amazonensis death through different pathways.

Synthesis, Antileishmanial Activity and Spin Labeling EPR Studies of Novel β-Carboline-Oxazoline and β-Carboline-Dihydrooxazine Derivatives

“…The β-carboline nucleus was prepared from commercial L-tryptophan (1) according to the methodology described by our research group. [14][15][16][17][18][19] The L-tryptophan methyl ester (2) was subjected to the condensation reaction of Pictet-Spengler with different aldehydes in acid medium, providing the methyl 1-(substituted-phenyl)-1,2,3,4-tetrahydro-9H-β-carboline-3-carboxylates 3a-3i, which were oxidized with sulfur under reflux in xylene to the methyl 1-(substituted-phenyl)-9H-β-carboline-3-carboxylates 4a-4i. The basic hydrolysis reaction of 4a-4i provided the 1-(substituted-phenyl)-9H-β-carboline-3-carboxylic acids 5a-5i.…”

“…In this context, our research group has already demonstrated the antileishmanial activity of β-carbolines containing substituents at 1-and 3-positions of the β-carboline nucleus. [14][15][16][17][18][19][20] In the works developed by Tonin et al 16 and Pedroso et al, 17 it was demonstrated the activity of N -alkyl-(1-phenylsubstitutedβ-carboline)-3-carboxamides against promastigote, axenic amastigote and intracellular amastigote forms of Leishmania amazonensis. The compound with the N-benzyl-carboxamide group at C-3 was active against promastigote and axenic amastigote forms with IC 50 (50% inhibitory concentration) values of 2.6 and 1.0 µM, respectively, 17 and killed L. amazonensis promastigotes through different cell death pathways, including apoptosis and autophagy.…”

“…The compound with the N-benzyl-carboxamide group at C-3 was active against promastigote and axenic amastigote forms with IC 50 (50% inhibitory concentration) values of 2.6 and 1.0 µM, respectively, 17 and killed L. amazonensis promastigotes through different cell death pathways, including apoptosis and autophagy. 18 Recently, the antileishmanial activity of β-carboline-1,3,5-triazine hybrids was reported by Baréa et al 19 Among the compounds tested, the hybrid II ( Figure 1) showed potent activity against the promastigote (IC 50 = 6.2 ± 1.4 µM, selectivity index (SI) = 23.5) and amastigote (IC 50 = 1.2 ± 0.5 µM, SI = 121.4) forms of L. amazonensis and exhibited low toxicity. Studies of action mechanism in promastigotes showed that compound II caused alterations in cell division cycle and an increase of lipid-storage bodies, leading the cells to death through various factors.…”

“…In the recent years, several studies have reported the antileishmanial activity of heterocyclic compounds, 3 including β-carbolines alkaloids. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Ashok et al, 13 for example, described the antileishmanial activity against Leishmania infantum and Leishmania donovani of a series of (1-phenyl-9H-pyrido [3,4-b]indol-3-yl) (4-phenylpiperazin-1-yl)methanone derivatives. Among the derivatives assayed, compound I ( Figure 1) displayed potent inhibition for both Leishmania species, with 50% effective concentration (EC 50 ) values ranging from 1.9 to 6.9 µM.…”

Estudo dos mecanismos de morte induzidos pelo complexo de rutênio hmxbato (cis-[RuII((ŋ2-O2CC7H7O2)(dppm)2]PF6) com atividade contra Leishmania (Leishmania) amazonensis e células tumorais de pulmão – A549

“…(3) perda do potencial mitocondrial; (4) modificações no ciclo celular e (5) liberação do citocromo C. Além dessas alterações moleculares, mudanças morfológicas típicas do processo apoptótico também são vistas em tripanosomatídeos, a saber: condensação da cromatina, fragmentação do DNA, encolhimento celular, formação de corpos apoptóticos e formação de blebbing na membrana plasmática (DEBRABANT et al, 2003;DUSZENKO et al, 2006;MENDES et al, 2016;MENNA-BARRETO, 2019). A tabela 1 mostra a comparação de fenótipos apoptóticos presentes em organismos multicelulares e tripanosomatídeos.…”