Cynaroside inhibits Leishmania donovani UDP-galactopyranose mutase and induces reactive oxygen species to exert antileishmanial response

Abstract

Cynaroside, a flavonoid, has been shown to have antibacterial, antifungal and anticancer activities. Here, we evaluated its antileishmanial properties and its mechanism of action through different in silico and in vitro assays. Cynaroside exhibited antileishmanial activity in time- and dose-dependent manner with 50% of inhibitory concentration (IC50) value of 49.49 ± 3.515 µM in vitro. It inhibited the growth of parasite significantly at only 20 µM concentration when used in combination with miltefosine, a standard drug which has very high toxicity. It also inhibited the intra-macrophagic parasite significantly at low doses when used in combination with miltefosine. It showed less toxicity than the existing antileishmanial drug, miltefosine at similar doses. Propidium iodide staining showed that cynaroside inhibited the parasites in G0/G1 phase of cell cycle. 2,7-dichloro dihydro fluorescein diacetate (H2DCFDA) staining showed cynaroside induced antileishmanial activity through reactive oxygen species (ROS) generation in parasites. Molecular-docking studies with key drug targets of Leishmania donovani showed significant inhibition. Out of these targets, cynaroside showed strongest affinity with uridine diphosphate (UDP)-galactopyranose mutase with −10.4 kcal/mol which was further validated by molecular dynamics (MD) simulation. The bioactivity, ADMET (absorption, distribution, metabolism, excretion and toxicity) properties, Organisation for Economic Co-operation and Development (OECD) chemical classification and toxicity risk prediction showed cynaroside as an enzyme inhibitor having sufficient solubility and non-toxic properties. In conclusion, cynaroside may be used alone or in combination with existing drug, miltefosine to control leishmaniasis with less cytotoxicity.

Sesamol Induces Apoptosis-Like Cell Death in Leishmania donovani

“…One possible source for such affordable treatment lies in the use of natural compounds purified from medicinal plants. Yet, many natural compounds, namely, quercetin, plumbagin, withanolide, cynaroside, and clerodane diterpene, have been evaluated for their antileishmanial potential (Fonseca-silva et al, 2011;Kathuria et al, 2014;Awasthi et al, 2016;Chandrasekaran et al, 2016;Tabrez et al, 2021). Many chemically synthesized compounds were also reported to have appreciable antileishmanial activity (Bekhit et al, 2018;Thompson et al, 2021).…”

Optimization of ultrasound‐assisted extraction parameters for improving content of acteoside, luteolin‐7‐ O ‐glucoside, and total polyphenols in extracts of Plantago lanceolata aerial parts

“…Acteoside is one of the most investigated compounds in Plantago genus and it showed various pharmacological activities such as antigenotoxic, gastric antiulcer, antiinflammatory, and woundhealing activities (Henn et al, 2019). On the other hand, luteolin-7-Oglucoside, that is reported as one of the main constituents of Cynara scolimus, demonstrated significant antimicrobial activity and reduced nephrotoxicity and ototoxicity (Tabrez et al, 2021). Also, it possesses anticarcinogenic potential and can be applied as a drug for colon carcinogenesis suppression (Žemlička et al, 2014).…”

Exploration of potential inhibitors for autophagy‐related protein 8 as antileishmanial agents

“…The predicted structure was further validated by the Ramachandran plot using PROCHECK (Laskowski et al, 1996). The receptor ( Ld atg8) and ligands were visualized by using Discovery studio (Rahman et al, 2021; Tabrez et al, 2020). Subsequently, the three‐dimensional protein structure of the Ld atg8 protein present in L .…”