Some novel antileishmanial compounds inhibit normal cell cycle progression of Leishmania donovani promastigotes and exhibits pro-oxidative potential.

In the midst of numerous setbacks that beclouds the fight against leishmaniasis; a neglected tropical disease, the search for new chemotherapeutics against this disease is of utmost importance. Leishmaniasis is a disease closely associated with poverty and endemic in Africa, Asia, southern Europe and the Americas. It is caused by parasites of the genus Leishmania and transmitted by a sandfly vector. In this study, we evaluated the antileishmanial potency of eighteen pathogen box compounds and elucidated their biosafety and possible mechanisms of action against Leishmania donovani promastigotes and amastigotes in vitro. IC50s range of 0.12±0.15 to >6.25 µg/ml and 0.13±0.004 to >6.25µg/ml were observed for the promastigotes and amastigotes, respectively. We demonstrated the ability of some of the compounds to cause cytocidal effect on the parasites, induce increased production of reactive oxygen species (ROS), disrupt the normal parasite morphology and cause the accumulation of parasites at the DNA synthesis phase of the cell cycle. We recommend a further in vivo study on these compounds to validate the findings.

Elucidating the possible mechanism of action of some pathogen box compounds against Leishmania donovani.

Leishmaniasis is one of the Neglected Tropical Diseases (NTDs) which is closely associated with poverty and has gained much relevance recently due to its opportunistic coinfection with HIV. It is a protozoan zoonotic disease transmitted by a dipteran Phlebotomus, Lutzomyia/ Sergentomyia sandfly; during blood meals on its vertebrate intermediate hosts. It is a four-faceted disease with its visceral form being more deadly if left untreated. It is endemic across the tropics and sub-tropical regions of the world. It can be considered the third most important NTD after malaria and lymphatic filariasis. Currently, there are numerous drawbacks on the fight against leishmaniasis which includes: non-availability of vaccines, limited availability of drugs, high cost of mainstay drugs and parasite resistance to current treatments. In this study, we screened the antileishmanial activity, selectivity, morphological alterations, cell cycle progression and apoptotic potentials of six Pathogen box compounds from Medicine for Malaria Venture (MMV) against Leishmania donovani promastigotes and amastigotes. From this study, five of the compounds showed great promise as lead chemotherapeutics based on their high selectivity against the Leishmania donovani parasite when tested against the murine mammalian macrophage RAW 264.7 cell line (with a therapeutic index ranging between 19-914 (promastigotes) and 1-453 (amastigotes)). The cell cycle progression showed growth arrest at the G0-G1 phase of mitotic division, with an indication of apoptosis induced by two (2) of the pathogen box compounds tested. Our findings present useful information on the therapeutic potential of these compounds in leishmaniasis. We recommend further in vivo studies on these compounds to substantiate observations made in the in vitro study.

Exploration of antiplasmodial activity in Acalypha wilkesiana Müller Argoviensis, 1866 (family: Euphorbiaceae) and its GC-MS fingerprint.

The plant kingdom continues to hold great promise for the eradication of Malaria infection following the challenges of insecticide resistance by the vector mosquito, drug resistance by the parasite, and the development of a vaccine still being a mirage. Acalypha wilkesiana Muller Argoviensis, 1866 (family: Euphorbiaceae) leaves have the ethnopharmacological reputation for use as a remedy against dermal microbial infections in Nigeria. Here, we have studied the antiplasmodial potential of the extract of the leaves of this ornamental plant. Aqueous methanol crude extract (70%) and Prep reversed-phase high-performance liquid chromatography (RPHPLC) fractions were tested in vitro against blood stage Plasmodium falciparum 3D7 strain parasites for antiplasmodial activity using the SYBR Green assay. Results obtained were validated through Giemsa stained microscopic blood smeared slides. An IC50 of < 0.39 µg/ml for fractions of the RPHPLC together with TC50 of > 100 µg/ml against mammalian HUH-7 cell lines and a HC50 of > 100 µg/ml against red blood cells indicate a high selectivity of this plant against Plasmodium. This is the first report of the antiplasmodial activity of this plant and a GC-MS fingerprinting of the same, opening the possibilities of identifying novel pharmacophores against the malaria parasite.