Abstract
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.
Highlights
Among the six neglected tropical diseases, lymphatic filariasis (LF) is one of the major health problems in 73 tropical and subtropical countries in Africa, Asia, South and Central America and the Pacific Islands
According to the World Health Organization (WHO) global report, over 120 million people are currently infected with LF [1,2] of which about 40 million people are suffering with chronic disease manifestations: Elephantiasis and hydrocele [3], which cause permanent, long-term disability and economic loss to the nations [3,4]
The CHCl3 extract was subjected to repeated chromatographic separations over vacuum liquid chromatographic separations (VLC) using TLC grade silica gel H, which resulted in the isolation of a major compound
Summary
Among the six neglected tropical diseases, lymphatic filariasis (LF) is one of the major health problems in 73 tropical and subtropical countries in Africa, Asia, South and Central America and the Pacific Islands. DEC and IVM both are microfilaricides with poor or no activity on adult parasites [9], the peripheral blood microfilaremia reappears in patients after a certain period of withdrawal of the drug. This depressing perspective demands, an urgent need for new molecular structures associated with macrofilaricidal activity/or sterilizing the adult worms is needed [8,9,10] as adult parasites produce millions of microfilariae (mf) that are picked up by the mosquito vector and transmitted, but are responsible for the debilitating pathological lesions. Macrofilaricidal agents are the need of hour, which adversely affect the target but should have very low or no side effect [11]
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