Antileishmanial Activity of 4,8-Dimethoxynaphthalenyl Chalcones on Leishmania amazonensis

Abstract

Leishmaniasis is a neglected tropical disease caused by Leishmania species. Available therapeutic options have several limitations. The drive to develop new, more potent, and selective antileishmanial agents is thus a major goal. Herein we report the synthesis and the biological activity evaluation against promastigote and amastigote forms of Leishmania amazonensis of nine 4,8-dimethoxynaphthalenyl chalcones. Compound ((E)-1-(4,8-dimethoxynaphthalen-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one), 4f, was the most promising with an IC50 = 3.3 ± 0.34 μM (promastigotes), a low cytotoxicity profile (CC50 = 372.9 ± 0.04 μM), and a high selectivity index (SI = 112.6). Furthermore, 4f induced several morphological and ultrastructural changes in the free promastigote forms, loss of plasma membrane integrity, and increased reactive oxygen species (ROS). An in silico analysis of drug-likeness and ADME parameters suggested high oral bioavailability and intestinal absorption. Compound 4f reduced the number of infected macrophages and the number of amastigotes per macrophage, with an IC50 value of 18.5 ± 1.19 μM. Molecular docking studies with targets, ARG and TR, showed that compound 4f had more hydrogen bond interactions with the ARG enzyme, indicating a more stable protein-ligand binding. These results suggest that 4,8-dimethoxynaphthalenyl chalcones are worthy of further study as potential antileishmanial drugs.

An Updated Review on Recent Advancements in the Diverse Biological Applications of Medicinally Privileged Scaffold: Chalcone and its derivatives

“…It was found to be a potent compound with a better IC50 value. The molecular docking studies also exhibited that the compound had more hydrogen bond interactions with the ARG enzyme and correlated with the experimental results 82 . Similarly, the antileishmanial activity of another chalcone derivative (90) was evaluated against L. amazonensis and was found to be exhibiting potent activity 83 .…”

Chalcone Derivative Induces Flagellar Disruption and Autophagic Phenotype in Phytomonas serpens In Vitro

“…In the context of the natural products’ mode of action, oxidative stress figures as one of the most recurrent processes directly involved in their biological effect. The increase in ROS production as a result of chalcones treatment was already reported in trypanosomatids [ 22 , 23 , 24 , 40 ]. Here, the compound NaF at IC 50 /24 h concentration induced a remarkable increase in ROS levels in P. serpens promastigotes, similar to that previously observed in T. cru z i and L. amazonensis treated with other plant secondary metabolites, sesquiterpenoids and flavonoids , respectively [ 41 , 42 ].…”

“…Michael addiction involving chalcone derivative and glutathione thiols have already being reported in human cancer cells, resulting in GSH depletion and ROS elevation [ 51 , 52 ]. Furthermore, recent in vitro and in silico studies suggest that chalcones are able to bind in crucial sites of trypanothione reductase (TR) and tryparedoxin peroxidase (TXNPx), affecting their activity which leads to increased ROS levels [ 22 , 23 , 24 , 40 ]. Thus, ROS accumulation observed in P. serpens after the treatment with the chalcone NaF could be derived from the parasite’s redox unbalance, rather than causing a secondary mitochondrial dysfunction.…”

“…Recently, chalcone (1,3-diaryl-2-propane-1-one), a phenolic precursor made up of an α β-unsaturated carbonyl system that joins two aromatic rings [ 16 ], and its derivatives have stood out [ 17 , 18 , 19 , 20 , 21 ]. The inhibitory activity of a large amount of chalcone derivatives has already been well-described against Leishmania , T. cruzi and T. brucei [ 22 , 23 , 24 ]. In these parasites, chalcones and its derivatives mainly affect the mitochondrion, causing structural alterations in this organelle, as well as cytoplasmic and nuclear changes including vacuolization and DNA fragmentation [ 25 , 26 ].…”

In Vitro and In Silico Evaluation of the Anti-leishmanial Activity of Novel Synthetic Chalcones

“…Studies with chalcone derivatives reveal that the anti-promastigote action of these substances may be related to the formation of pores in the parasite cell membrane, as well as alterations in the membranes involving cellular structures, such as mitochondria, and damage to the parasites' DNA [28][29][30]. These results suggest that these mechanisms may be potentially responsible for the action of the chalcones tested in this study, and still need to be investigated for the molecules of the present work.…”