Ketamine can be produced by Pochonia chlamydosporia: an old molecule and a new anthelmintic?

BACKGROUND: Infection by nematodes is a problem for human health, livestock, and agriculture, as it causes deficits in host health, increases production costs, and incurs a reduced food supply. The control of these parasites is usually done using anthelmintics, which, in most cases, have not been fully effective. Therefore, the search for new molecules with anthelmintic potential is necessary. METHODS: In the present study, we isolated and characterized molecules from the nematophagous fungus Pochonia chlamydosporia and tested these compounds on three nematodes: Caenorhabditis elegans; Ancylostoma ceylanicum; and Ascaris suum. RESULTS: The ethyl acetate extract showed nematicidal activity on the nematode model C. elegans. We identified the major substance present in two sub-fractions of this extract as ketamine. Then, we tested this compound on C. elegans and the parasites A. ceylanicum and A. suum using hamsters and mice as hosts, respectively. We did not find a difference between the animal groups when considering the number of worms recovered from the intestines of animals treated with ketamine (6 mg) and albendazole (P > 0.05). The parasite burden of larvae recovered from the lungs of mice treated with ketamine was similar to those treated with ivermectin. CONCLUSIONS: The results presented here demonstrate the nematicidal activity of ketamine in vitro and in vivo, thus confirming the nematicidal potential of the molecule present in the fungus P. chlamydosporia may consist of a new method of controlling parasites.

Leishmanicidal and cytotoxic activity of hederagenin-bistriazolyl derivatives.

Aiming to obtain new potent leishmanicidal and cytotoxic compounds from natural sources, the triterpene hederagenin was converted into several new 1,2,3-triazolyl derivatives tethered at C-23 and C-28. For this work hederagenin was isolated from fruits of Sapindus saponaria and reacted with propargyl bromide to afford as a major product bis-propargylic derivative 1 in 74%. Submitting this compound to Huisgen 1,3-dipolar cycloaddition reactions with several azides afforded the derivatives 2-19 with yields in the range of 40-87%. All compounds have been screened for in vitro cytotoxic activity in a panel of five human cancer cell lines by a SRB assay. The bioassays showed that compound 19 was the most cytotoxic against all human cancer cell lines with EC50 = 7.4-12.1 µM. Moreover, leishmanicidal activity was evaluated through the in vitro effect in the growth of Leishmania infantum, and derivatives 1, 2, 5 and 17 were highly effective preventing proliferation of intracellular amastigote forms of L. infantum (IC50 = 28.8, 25.9, 5.6 and 7.4 µM, respectively). All these compounds showed a higher selectivity index and low toxicity against two strains of kidney BGM and liver HepG2 cells. Compound 5 has higher selectivity (1780 times) in comparison with the commercial antimony drug and is around 8 times more selective than the most active compound previously reported hederagenin derivative. Such high activity associated with low toxicities make the new bis-traiazolyl derivatives promising candidates for the treatment of leishmaniasis. In addition, hederagenin and some derivatives (2, 5 and 17) showed interaction in the binding site of the enzyme CYP51Li.

Highly potent anti-leishmanial derivatives of hederagenin, a triperpenoid from Sapindus saponaria L.

Leishmaniasis is a neglected tropical disease (NTDs), endemic in 88 countries that affect more than 12 million people. Current drugs are limited due to their toxicity, development of biological resistance, length of treatment and high cost. Thus, the search for new effective and less toxic treatments is an urgent need. In this study, we report the synthesis of 3 new amide derivatives of hederagenin (22-24) with yields between 70% and 90%, along with 57 other derivatives of hederagenin (1-21, 25-60) carrying different groups at C-28 previously reported by our group, and the results of their in vitro ability to inhibit the growth of Leishmania infantum. Some derivatives (3, 4, 44, 49 and 52), showed activity at micromolar level and low toxicity against BGM and HepG2 cells. Moreover, the ability of hederagenin derivatives 3 (IC50 = 9.7 µM), 4 (12 µM), 44 (11 µM) and 49 (2 µM), to prevent proliferation of intracellular amastigote forms of L. infantum and their higher selectivity index and low toxicity compared to commercial positive drug control of choice (potassium antimonyl tartrate trihydrate) (IC50 = 80 µM, SI = 0.1), make these compounds promising candidates for the treatment of leishmaniasis.