Abstract
Cutaneous leishmaniasis (CL) is a neglected tropical disease, which causes severe skin lesions. Due to the lack of effective vaccines, and toxicity or reduced effectiveness of available drugs in addition to complex and prolonged treatments, there is an urgent need to develop alternatives for the treatment for CL with different mechanisms of action. In our effort to search for new promising hits against Leishmania parasites we prepared 18 acyl hydrazone derivatives of thiochroman-4-ones. Compounds were evaluated for their in vitro antileishmanial activity against the intracellular amastigote form of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2). Our results show that derivatization of the thiochroman-4-ones with acyl hydrazones significantly enhances the antileishmanial activity. Among the compounds tested semicarbazone and thiosemicarbazone derivatives of thioflavanone 19 and 20 displayed the highest antileishmanial activities, with EC50 values of 5.4 and 5.1 µM and low cytotoxicities (100.2 and 50.1 µM respectively), resulting in higher indexes of selectivity (IS).
Highlights
Leihsmaniasis is a parasitic disease caused by various species of protozoans of the genusLeishmania [1]
In our search for new chemotherapeutic alternatives to fight leishmaniasis we have explored thiochroman compounds, which could be considered a potential privileged scaffold [5,6] because of its great similarity with the chroman compounds which display a broad range of bioactivities [7]
Thioflavanone 5 displayed moderate antileishmanial activity and high cytotoxic activity resulting in a low indexes of selectivity (IS)
Summary
Leihsmaniasis is a parasitic disease caused by various species of protozoans of the genusLeishmania [1]. Because of the high occurrence, severe side effects of existing therapies and the lack of therapeutic alternatives the World Health Organization (WHO) considers leishmaniasis a neglected tropical disease and has encouraged countries to search for new antileishmanial drugs with novel mechanisms of action [1,4]. Numerous hydrazones have been reported to possess interesting biological activities such as antitumoral, antiviral and antiparasitic effects [8,9,10]; some hydrazones exhibit activity against the parasites that cause malaria, leishmaniasis and Chagas disease [3,11,12,13,14,15,16,17,18], where the inhibition of proteases and represent the most common mechanism of action for the hydrazones [16,19,20,21]
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