Investigation of 8-methoxy-3-(4-nitrobenzoyl)-6-propyl-2H-chromen-2-one as a promising coumarin compound for the development of a new and orally effective antileishmanial agent.

Changes in host immunity and parasite resistance to drugs are among the factors that contribute to decreased efficacy of antiparasitic drugs such as the antimonial compounds pentamidine, amphotericin (AMP B) and miltefosine. Bioactive natural products could be alternatives for the development of new drugs to treat neglected human diseases such as leishmaniasis. Natural coumarins and synthetic analogues have shown leishmanicidal activity, mainly in vitro. This study investigated the in vitro and in vivo leishmanicidal activity of synthetic coumarin compounds (C1-C5) in parasites Leishmania (L.) amazonensis and L. (L.) infantum chagasi. The cytotoxicity of these compounds in mammalian cells and their influence on production of reactive oxygen species was also investigated. In vitro assays showed that 8-methoxy-3-(4-nitrobenzoyl)-6-propyl-2H-chromen-2-one (C4) was as active as AMP B mainly in the amastigote form (p < 0.05); C4 presented a selectivity index (65.43) four times higher than C2 (15.4) in L. amazonensis and six times higher (33.94) than C1 (5.46) in L. infantum chagasi. Additionally, coumarin C4 reduced the H2O2 concentration 32.5% more than the control group in L. amazonensis promastigotes during the lag phase of proliferation. No interference of C4 was observed on the mitochondrial membrane potential of the parasites. In vivo, coumarin C4 in corn oil (oral route) led to a reduction in the number of amastigotes from L. infantum chagasi to 1.31 × 106 and 4.09 × 104 in the spleen and liver, respectively (p < 0.05). Thus, C4 represents a candidate for further studies aiming at new treatments of leishmaniasis.

Synthesis and evaluation of the antileishmanial activity of silver compounds containing imidazolidine-2-thione.

A new series of silver compounds could be of interest on designing new drugs for the treatment of leishmaniasis. The compounds [Ag(phen)(imzt)]NO3(1), [Ag(phen)(imzt)]CF3SO3(2), [Ag(phen)2](BF4)·H2O (3), [Ag2(imzt)6](NO3)2(4), and imzt have been synthesized and evaluated in vitro for antileishmanial activity against Leishmania. (L.) amazonensis (La) and L. (L.) chagasi (Lc), and two of them were selected for in vivo studies. In addition to investigating the action on Leishmania, their effects on the hydrogen peroxide production and cysteine protease inhibition have also been investigated. As for antileishmanial activity, compound (4) was the most potent against promastigote and amastigote forms of La (IC50 = 4.67 and 1.88 µM, respectively) and Lc (IC50 = 9.35 and 8.05 µM, respectively); and comparable to that of amphotericin B, reference drug. Beside showing excellent activity, it also showed a low toxicity. In the in vivo context, compound (4) reduced the number of amastigotes in the liver and spleen when compared to the untreated group. In evaluating the effect of the compounds on Leishmania, the level of hydrogen peroxide production was maintained between the lag and log phases; however, in the treatment with compound (4) it was possible to observe a reduction of 25.44 and 49.13%, respectively, in the hydrogen peroxide rates when compared to the lag and log phases. It was noticed that the presence of a nitrate ion and imzt in compound (4) was important for the modulation of the antileishmanial activity. Thus, this compound can represent a potentially new drug for the treatment of leishmaniasis.

Leishmanicidal and antimicrobial activity of primin and primin-containing extracts from Miconia willdenowii.

As a part of an ongoing bioprospective project, searching for potential medicinal plants from the Brazilian Atlantic Forest, Miconia willdenowii was selected for its potential leishmanicidal and antimicrobial activities. The crude ethanolic extract of M. willdenowii showed an inhibition of 99.7% of the promastigote forms of Leishmania amazonensis at the concentration of 80 µg/mL. Further investigation of its antimicrobial activity against pathogenic fungi and Gram positive and negative bacteria, revealed a significant antimicrobial activity. A bioguided study with its liquid-liquid partition fractions revealed the hexane fraction (Hex) as the most active against Leishmania, inhibiting 99.2% and 46.9% of the protozoan at concentrations of 40 and 20 µg/mL, respectively. Hex also showed significant antimicrobial activity against Staphylococcus aureus and Candida krusei with IC50 of 15.6 and 62.5 µg/mL, respectively. Purification of Hex led to the isolation of 2-methoxy-6-pentyl-benzoquinone (1, also known as primin) as the active metabolite, probably responsible for the observed antimicrobial and anti-leishmania effects. Primin (1) disclosed leishmanicidal activity (IC50 = 1.25 µM), showing higher potency than the standard drug amphotericin B (IC50 = 5.08 µM), with additional antifungal effects against all tested fungi species. Compound 1 also showed significant activity against S. aureus (IC50 = 8.94 µM), showing a comparable potency with the reference drug chloramphenicol (IC50 = 6.19 µM), but with a potential cytotoxicity towards peripheral human blood mononuclear cells (CC50 = 255.15 µM). Here in, the antimicrobial and anti-L. amazonensis effects of M. willdenowii are reported for the first time, as well as Primin (1) as its probable bioactive metabolite.

Leishmanicidal, antiproteolytic, and mutagenic evaluation of alkyltriazoles and alkylphosphocholines.

A series of 16 simple long-chain alkyltriazoles and two novel alkylphosphocholine derivatives containing an azide moiety were evaluated in vitro for their leishmanicidal activity against. Among the 18 compounds tested, the eight most active compounds against promastigote forms were selected for further evaluation against amastigote forms. These compounds were also evaluated for their cytotoxicity against murine macrophages and tested as inhibitors of cysteine protease rCPB2.8, an important target for development of antileishmanial drugs. The mutagenicity of some of these compounds was also evaluated in prokaryotic and eukaryotic cells to assess any genetic effects of the leishmanicidal candidates. The compound 4, an alkylphosphocholine derivative, was found to be the most potent against amastigote forms with an IC50 of 3.81 µM, comparable to that of pentamidine (IC50 = 6.62 µM) and amphotericin B (IC50 = 6.10 µM), two established leishmanicidal drugs. Compound 4 also exhibited the best selectivity index (SI) values of the series, demonstrating low toxicity against macrophages and a cLogP value higher than 5. Among the alkyltriazoles, compounds 13 and 14 were the most active against promastigote and amastigote forms. They were then evaluated for their mutagenicity in vitro; the mutagenicity index (MI) values were lower than 2, suggesting that these compounds are not mutagenic.