Chalcones identify cTXNPx as a potential antileishmanial drug target

Abstract

With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2’,6’-dihydroxy-4’-methoxychalcone (DMC), the nitro-analogue, 3-nitro-2’,4’,6’- trimethoxychalcone (NAT22, 1c) was identified as potent broad spectrum antileishmanial drug lead. Structural modification provided an alkyne containing chemical probe that labelled a protein within the parasite that was confirmed as cytosolic tryparedoxin peroxidase (cTXNPx). Crucially, labelling is observed in both promastigote and intramacrophage amastigote life forms, with no evidence of host macrophage toxicity. Incubation of the chalcone in the parasite leads to ROS accumulation and parasite death. Deletion of cTXNPx, by CRISPR-Cas9, dramatically impacts upon the parasite phenotype and reduces the antileishmanial activity of the chalcone analogue. Molecular docking studies with a homology model of in-silico cTXNPx suggest that the chalcone is able to bind in the putative active site hindering access to the crucial cysteine residue. Collectively, this work identifies cTXNPx as an important target for antileishmanial chalcones.

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

“…Furthermore, it is in medicinal chemistry that chalcones are rightfully considered to have a privileged structure [ 5 ], since the chalcone core is present in a variety of important bioactive compounds with a broad spectrum of pharmacological activities, such as antimalarial, antibacterial, anticancer, anti-inflammatory, antiplasmodial, antioxidant, antifungal, antitubercular and antiviral agents [ 5 , 6 ]. Furthermore, recent reports have further indicated that chalcone derivatives ( Figure 1 ) may also be a promising pharmacophoric group against diseases caused by protozoa, including leishmaniasis [ 7 , 8 , 9 , 10 ].…”

Total Synthesis of the Natural Chalcone Lophirone E, Synthetic Studies toward Benzofuran and Indole-Based Analogues, and Investigation of Anti-Leishmanial Activity

“…The antileishmanial activity of chalcones has been largely investigated through phenotypic assays. The mode of action of synthetic and natural chalcones has not been elucidated yet, even though some targets, such as the arginase enzyme or enzymes involved in the trypanothione metabolic pathways [14][15][16], have been postulated. In addition, licochalcone A has been shown to alter the ultrastructure of the mitochondria and to inhibit the activity of fumarate reductase in the respiratory chain of L. major promastigote [17,18] Molecules 2022, 26…”

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 ].…”