Antileishmanial Activity Of Compounds Research Articles

Isolation of Sesquiterpenoids and Steroids from the Soft Coral Sinularia brassica and Determination of Their Absolute Configuration.

Two undescribed rearranged cadinane-type sesquiterpenoids (1–2), named sinulaketol A-B, together with one new chlorinated steroid (3), one new gorgosterol (4), one known sesquiterpene (5), one known dibromoditerpene (6) and two known polyhydroxylated steroids (7–8) were isolated from the soft coral Sinularia brassica. The structures of these compounds were established by extensive spectroscopic analysis, including HRESIMS, 1D, and 2D NMR spectroscopy. Their absolute configurations were also determined by the ECD calculations and DP4+ probability analysis. Antileishmanial activity of compounds 1–8 was evaluated in vitro against the amastigote forms of Leishmania donovani, in which compounds 3, 6, and 7 inhibited the growth of L. donovani by 58.7, 74.3, 54.7%, respectively, at a concentration of 50 μM. Antimicrobial effect of the isolated compounds were also evaluated against Candida albicans, Staphylococcus aureus, and Escherichia coli. Compound 6, a brominated diterpene, exhibited antimicrobial effect against S. aureus.

Toxicity and Anti-promastigote Activity of Benzoxazinoid Analogs Against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum.

Purpose: Here, we aim to evaluate the antileishmanial activity of compounds with a benzoxazinoid (BX) skeleton, previously synthesized by our group, against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum promastigotes. Methods: Anti-promastigote activity, as well as cytotoxicity, were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assays. The selectivity index (SI) for each compound was calculated using a ratio of the cytotoxicity of compounds and the geometric mean (GM) of antileishmanial concentrations to each species tested. The comparisons between groups were carried out using a t test or analysis of variance (one-way ANOVA). A P value of less than 0.05 was considered significant. Results: All the compounds tested were active, with IC50 falling between 92±6.19 µg/mL and 238±6.57 µg/mL for L. braziliensis, and 89±6.43 µg/mL and 188±3.58 µg/mL against L. infantum. Bex2, Bex3, Pyr1, Pyr2, and Pyr4 were compounds that showed activity similar to the drug Glucantime®, exhibited low cytotoxicity against splenic hamster cells (CC50 raging between >400 and 105.7±2.26 µg/mL) and had favorable selectivity indices (SI 1.12 to 3.96). Conclusion: The analogs in question are promising prototypes for the pharmaceutical development of novel, safer and more effective leishmanicidal agents.

Antiplasmodial and antileishmanial activities of compounds from Piper tuberculatum Jacq fruits.

This study assessed the activity of compounds from Piper tuberculatum against Plasmodium falciparum and Leishmania guyanensis. The effects of compounds from P. tuberculatum fruits on P. falciparum and L. guyanensis promastigote growth in vitro were determined. Hemolytic action and cytotoxicity in HepG2 and J774 cells were measured. Three compounds showed strong antiplasmodial activity and one compound showed strong antileishmanial activity. Two compounds were non-toxic to HepG2 cells and all were toxic to J774 cells. The compounds showed no hemolytic activity. The tested compounds from P. tuberculatum exhibited antiparasitic and cytotoxic effects.

Synthesis and In vitro Leishmanicidal Activities of Six Quercetin Derivatives.

Background:Today, leishmaniasis is a widespread, infectious parasitic disease caused by Leishmania spp. Natural-derived compounds are likely to provide a valuable source of new pharmaceuticals, and among them, quercetin derivatives may have antileishmanial effects. The antileishmanial activity of 3,5,7,3’,4’-pentahydroxyflavonol (quercetin) derivatives is partly attributed to the position and pKa of phenolic or catechol hydroxyl groups. Therefore, to optimize their leishmanicidal effect, the structural features of quercetin and its derivatives were improved by acylation or alkylation of hydroxyl groups and changing their pKa and consequently their activities.Materials and Methods:In this study, during a regioselective method, quercetin derivatives were synthesized. The structures of synthesized compounds were confirmed by mass, IR, 1H-, and 13C-NMR spectral data. The antileishmanial activities of compounds 1–6 were compared with glucantime as the standard drug against promastigotes of Leishmania major using standard cell-based leishmanicidal assay.Results:In this study, during a regioselective method, two 7-O-quercetin derivatives (5 and 6), and three quercetin acetate derivatives (2, 3, and 4) were synthesized. In detail, the IC50 values found against L. major were (1) 2.5 ± 0.92; (2) 2.85 ± 0.99; (3) 15.5 ± 1.95; (4) 13.5 ± 3.5; (5) 2.6 ± 0.57; and (6) 1.3 ± 0.35 μM while IC50 value of glucantime as the standard drug was 88.5 ± 9.47 μM.Conclusions:The present study showed an effective antileishmanial activity of quercetin semisynthetic compounds (1–6) against in vitro promastigotes of L. major. Among them, quercetin analogs with more lipophilic and iron-chelating activity showed more antiparasite activity.

Bioactive phloroglucinols from Mallotus oppositifolius

The two new acylphloroglucinol derivatives, methylene-bis-aspidinol AB (1) and mallopposinol (2), together with the nine known compounds, aspidinol B (3), methylene-bis-aspidinol (4), (+)-α-tocopherol (5), lupeol (6), stigmasterol (7), phytol (8), bergenin (9), squalene (11) and methyl gallate (10) were isolated from the leaves of Mallotus oppositifolius. Their structures were elucidated by spectral analysis including MS, 1D and 2D-NMR spectroscopy. In vitro trypanocidal and antileishmanial activities of compounds 1–9 were evaluated. Mallopposinol (2) and aspidinol B (3) displayed weak antileishmanial activities against Leishmania donovani promastigotes, with EC50 values of 21.3 and 38.8μM, respectively. Only the methylene-bis-aspidinol (4) exhibited trypanocidal activity against Trypanosoma brucei brucei trypomastigotes (LC100=0.8μM) similar to the reference drug pentamidine (LC100=0.4μM).

Secondary Metabolites from the Fungus Emericella Nidulans

A new polyketide derivative koninginin H (1), has been isolated from the fungus Emericella nidulans, together with koninginin E (2), koninginin A (3), trichodermatide B (4), citrantifidiol (5), (4S,5R)-4-hydroxy-5-methylfuran-2-one (6), the glycerol derivatives gingerglycolipid B (7), (2S)-bis[9Z,12Z]-1-O, 2-O-dilinoleoyl-3-O-[alpha-D-galactopyranosyl-(1" --> 6') beta-D-galactopyranosyl]glycerol (8), (2S)-bis[9Z,12Z]-1-O, 2-O-dilinoleoyl-3-O-beta-D-galactopyranosylglycerol (9), the cerebroside flavuside B (10), and the known sterols beta-sitosterol glucoside and ergosta-5,7,22-trien-3-ol. Their structures were established by extensive NMR studies (1H NMR, 13C NMR, DEPT, 1H-1H COSY, HSQC, HMBC) and mass spectrometry. The antibacterial, antimalarial, antifungal and antileishmanial activities of compounds 1-10 were examined and the results indicated that compound 4 showed good antifungal activity against Cryptococcus neoformans with an IC50 value of 4.9 microg/mL.

Antimicrobial and antiprotozoal activities of secondary metabolites from the fungus Eurotium repens.

In this study, we examined in vitro antibacterial, antifungal, antimalarial, and antileishmanial activities of secondary metabolites (1-8) isolated from the fungus Eurotium repens. All compounds showed mild to moderate antibacterial or antifungal or both activities except 7. The activity of compound 6 was the best of the group tested. The in vitro antimalarial evaluation of these compounds revealed that compounds 1-3, 5, and 6 showed antimalarial activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum with IC(50) values in the range of 1.1-3.0 μg/ml without showing any cytotoxicity to the mammalian cells. Compound 5 displayed the highest antimalarial activity. Antileishmanial activity against Leishmania donovani promastigotes was observed for compounds 1-6 with IC(50) values ranging from 6.2 to 23 μg/ml. Antileishmanial activity of compounds 5 and 6 (IC(50) values of 7.5 and 6.2 μg/ml, respectively) was more potent than 1-4 (IC(50) values ranging from 19-23 μg/ml). Compounds 7 and 8 did not show any antiprotozoal effect. Preliminary structure and activity relationship studies indicated that antibacterial, antifungal, antimalarial, and antileishmanial activities associated with phenol derivates (1-6) seem to be dependent on the number of double bonds in the side chain, which would be important for lead optimization in the future.

Quantitative structure–activity relationship study of phloroglucinol-terpene adducts as anti-leishmanial agents

Phloroglucinol class of natural products occur widely in Myrtaceae family and possess variety of biological activities viz. antimicrobial, antimalarial, cancer chemopreventive, anti-HIV and anti-leishmanial. In the present article, quantitative structure-activity relationship (QSAR) study was carried out for a series of phloroglucinol-terpene adducts exhibiting anti-leishmanial activity to find out the structural features which are crucial for the biological activity. The QSAR study was carried out using JChem for Excel and the best QSAR model was derived by multiple regression analysis. The best model of four descriptors yields squared correlation coefficient of 0.930 (s=0.096, F=65.93, P<0.0001) based on stepwise multiple regression method. The predictive ability of model was checked by cross validation method. The study indicated that the lipophilic character (CLogP), isoelectric point, Haray index and Platt index play important role in anti-leishmanial activity of compounds. Anti-leishmanial activity of several structurally similar naturally occurring euglobals has also been predicted using developed QSAR model.

Toxicity of betulin derivatives and in vitro effect on promastigotes and amastigotes of Leishmania infantum and L. donovani

The toxicity and antileishmanial activity of 20 betulin derivatives were studied. The toxicity of betulin and synthesized compounds was determined using a bacterial test (Microtox) and two mammalian cell lines (CHO-K1 and J774). The antileishmanial activity of compounds (50 μM) was examined in both the promastigote and intracellular amastigote stages of Leishmania infantum and L. donovani. No correlation was found among the toxicity tests. All the compounds showed significant antipromastigote activity. The antiproliferative capacity of derivatives was dependent on the parasite stage studied, and no substantial differences were found between Leishmania species. Betulin, 3,28-di-O-acetylbetulin and L-aspartyl amide of betulonic acid showed moderate activity against amastigotes. The highest inhibition of intracellular amastigote multiplication was achieved with a low micromolar concentration (IC(50) ca 9 μM) of heterocyclic betulin derivative 3,28-di-O-acetyllup-13(18)-ene with N-ethyltriazolo moiety 16, without significant toxicity for mammalian cells. These results point to the interest of this lead compound for further in vitro and in vivo tests.