Abstract
Malaria is one of the most prevailing fatal diseases causing between 1.2 and 2.7 million deaths all over the world each year. Further, development of resistance against the frontline anti-malarial drugs has created an alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-malarial agents possessing novel modes of action. Over the past few years triterpenoids from higher plants have shown a wide range of anti-malarial activities. As a part of our drug discovery program for anti-malarial agents from Indian medicinal plants, roots of Glycyrrhiza glabra were chemically investigated, which resulted in the isolation and characterization of 18β-glycyrrhetinic acid (GA) as a major constituent. The in vitro studies against P. falciparum showed significant (IC50 1.69µg/ml) anti-malarial potential for GA. Similarly, the molecular docking studies showed adequate docking (LibDock) score of 71.18 for GA and 131.15 for standard anti-malarial drug chloroquine. Further, in silico pharmacokinetic and drug-likeness studies showed that GA possesses drug-like properties. Finally, in vivo evaluation showed a dose dependent anti-malarial activity ranging from 68–100% at doses of 62.5–250mg/kg on day 8. To the best of our knowledge this is the first ever report on the anti-malarial potential of GA. Further work on optimization of the anti-malarial lead is under progress.
Highlights
Malaria is an endemic infection caused by the protozoan parasites belonging to the genus Plasmodium [1]
Some of the new drug targets identified in P. falciparum are Plasmodium falciparum lactate dehydrogenase enzyme, type II fatty acid synthase and plasmepsin
The Plasmodium falciparum lactate dehydrogenase enzyme (pfLDH) has significantly different structural and kinetic properties compared to human LDH iso-forms [6], but the LDH enzymes found in P. vivax, P. malariae and P. ovale all exhibit, ~ 90% identity to pfLDH and several selective inhibitors of pLDH have demonstrated anti-malarial activity in-vitro and in-vivo
Summary
Malaria is an endemic infection caused by the protozoan parasites belonging to the genus Plasmodium [1]. The recommended preventive drugs are a combination of sulfadoxine, pyramethamine and amodiaquine, while the therapeutic strategy includes use of artemisinin combinations in areas where P. falciparum is endemic and chloroquine (CQ) in the areas where it is still efficacious such as some American regions [2] This enormous global health challenge is partly due to the development of resistance against the frontline drugs especially artemisinins, which has been recently detected in the four countries of the Asian sub-continent. As a part of our drug discovery program on antimalarial agents from Indian medicinal plants, the literature search revealed significant anti-malarial activity in pentacyclic triterpenes, betulinic, oleanolic and ursolic acids [17,18]. The present study reports isolation and characterization of 18β-glycyrrhetinic acid (GA) as a major constituent from the roots of G. glabra followed by its in-vitro, in-silico and in vivo anti-malarial evaluation as shown in the Figure 1
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