In vitro, in silico and in vivo studies of ursolic acid as an anti-filarial agent

• Published in: PloS one Vol. 9; no. 11; p. e111244
• Main Authors: Kalani, Komal, Kushwaha, Vikas, Sharma, Pooja, Verma, Richa, Srivastava, Mukesh, Khan, Feroz, Murthy, P K, Srivastava, Santosh Kumar
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.11.2014; Public Library of Science (PLoS)
• Subjects: Acids; Analysis; Animals; Binding sites; Biology; Biology and Life Sciences; Brugia malayi; Brugia malayi - drug effects; Brugia timori; Chromatography; Computer and Information Sciences; Computer Simulation; Cytotoxicity; Drug discovery; Drugs; Engineering and Technology; Eucalyptus; Eucalyptus tereticornis; Filariasis - drug therapy; Filaricides - pharmacology; Filaricides - therapeutic use; Glutathione; Glutathione transferase; Humans; In Vitro Techniques; In vivo methods and tests; Ivermectin; Leaves; Medicinal plants; Medicine and Health Sciences; Meriones unguiculatus; Metabolism; Molecular docking; Parasites; Parasitology; Pharmaceutical sciences; Pharmacokinetics; Pharmacology; Plant Leaves; Plants, Medicinal; Research and Analysis Methods; Sterility; Studies; Triterpenes - pharmacology; Triterpenes - therapeutic use; Tropical diseases; Ursolic Acid; Wuchereria bancrofti
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0111244

As part of our drug discovery program for anti-filarial agents from Indian medicinal plants, leaves of Eucalyptus tereticornis were chemically investigated, which resulted in the isolation and characterization of an anti-filarial agent, ursolic acid (UA) as a major constituent. Antifilarial activity of UA against the human lymphatic filarial parasite Brugia malayi using in vitro and in vivo assays, and in silico docking search on glutathione-s-transferase (GST) parasitic enzyme were carried out. The UA was lethal to microfilariae (mf; LC100: 50; IC50: 8.84 µM) and female adult worms (LC100: 100; IC50: 35.36 µM) as observed by motility assay; it exerted 86% inhibition in MTT reduction potential of the adult parasites. The selectivity index (SI) of UA for the parasites was found safe. This was supported by the molecular docking studies, which showed adequate docking (LibDock) scores for UA (-8.6) with respect to the standard antifilarial drugs, ivermectin (IVM -8.4) and diethylcarbamazine (DEC-C -4.6) on glutathione-s-transferase enzyme. Further, in silico pharmacokinetic and drug-likeness studies showed that UA possesses drug-like properties. Furthermore, UA was evaluated in vivo in B. malayi-M. coucha model (natural infection), which showed 54% macrofilaricidal activity, 56% female worm sterility and almost unchanged microfilaraemia maintained throughout observation period with no adverse effect on the host. Thus, in conclusion in vitro, in silico and in vivo results indicate that UA is a promising, inexpensive, widely available natural lead, which can be designed and developed into a macrofilaricidal drug. To the best of our knowledge this is the first ever report on the anti-filarial potential of UA from E. tereticornis, which is in full agreement with the Thomson Reuter's 'Metadrug' tool screening predictions.