Deoxymikanolide

Asteraceae Plants as Sources of Compounds Against Leishmaniasis and Chagas Disease.[Pubmed:31156427]

Front Pharmacol. 2019 May 8;10:477.

Leishmaniasis and Chagas disease cause great impact on social and economic aspects of people living in developing countries. The treatments for these diseases are based on the same regimen for over 40 years, thus, there is an urgent need for the development of new drugs. In this scenario, Asteraceae plants (a family widely used in folk medicine worldwide) are emerging as an interesting source for new trypanocidal and leishmanicidal compounds. Herein, we provide a non-exhaustive review about the activity of plant-derived products from Asteraceae with inhibitory action toward Leishmania spp. and T. cruzi. Special attention was given to those studies aiming the isolation (or identification) of the bioactive compounds. Ferulic acid, rosmarinic acid, and ursolic acid (Baccharis uncinella DC.) were efficient to treat experimental leishmaniasis; while Deoxymikanolide (Mikania micrantha) and (+)-15-hydroxy-labd-7-en-17-al (Aristeguietia glutinosa Lam.) showed in vivo anti-T. cruzi action. It is also important to highlight that several plant-derived products (compounds, essential oils) from Artemisia plants have shown high inhibitory potential against Leishmania spp., such as artemisinin and its derivatives. In summary, these compounds may help the development of new effective agents against these neglected diseases.

Primary targets of the sesquiterpene lactone deoxymikanolide on Trypanosoma cruzi.[Pubmed:30668348]

Phytomedicine. 2019 Mar 15;56:27-34.

BACKGROUND: Deoxymikanolide is a sesquiterpene lactone isolated from Mikania micrantha and M. variifolia which, has previously demonstrated in vitro activity on Trypanosoma cruzi and in vivo activity on an infected mouse model. PURPOSE: Based on these promising findings, the aim of this study was to investigate the mechanism of action of this compound on different parasite targets. METHODS: The interaction of Deoxymikanolide with hemin was examined under reducing and non- reducing conditions by measuring modifications in the Soret absorption band of hemin; the thiol interaction was determined spectrophotometrically through its reaction with 5,5'-dithiobis-2-nitrobenzoate in the presence of glutathione; activity on the parasite antioxidant system was evaluated by measuring the activity of the superoxide dismutase and trypanothione reductase enzymes, together with the intracellular oxidative state by flow cytometry. Superoxide dismutase and trypanothione reductase activities were spectrophotometrically tested. Cell viability, phosphatidylserine exposure and mitochondrial membrane potential were assessed by means of propidium iodide, annexin-V and rhodamine 123 staining, respectively; sterols were qualitatively and quantitatively tested by TLC; ultrastructural changes were analyzed by transmission electron microscopy. Autophagic cells were detected by staining with monodansylcadaverine. RESULTS: Deoxymikanolide decreased the number of reduced thiol groups within the parasites, which led to their subsequent vulnerability to oxidative stress. Treatment of the parasites with the compound produced a depolarization of the mitochondrial membrane even though the plasma membrane permeabilization was not affected. Deoxymikanolide did not affect the intracellular redox state and so the mitochondrial dysfunction produced by this compound could not be attributed to ROS generation. The antioxidant defense system was affected by Deoxymikanolide at twenty four hours of treatment, when both an increased oxidative stress and decreased activity of superoxide dismutase and trypanothione reductase (40 and 60% respectively) were observed. Both the oxidative stress and mitochondrial dysfunction induce parasite death by apoptosis and autophagy. CONCLUSION: Based on our results, Deoxymikanolide would exert its anti-T cruzi activity as a strong thiol blocking agent and by producing mitochondrial dysfunction.

Assessment of sesquiterpene lactones isolated from Mikania plants species for their potential efficacy against Trypanosoma cruzi and Leishmania sp.[Pubmed:28945741]

PLoS Negl Trop Dis. 2017 Sep 25;11(9):e0005929.

Four sesquiterpene lactones, mikanolide, Deoxymikanolide, dihydromikanolide and scandenolide, were isolated by a bioassay-guided fractionation of Mikania variifolia and Mikania micrantha dichloromethane extracts. Mikanolide and Deoxymikanolide were the major compounds in both extracts (2.2% and 0.4% for Mikania variifolia and 21.0% and 6.4% for Mikania micrantha respectively, calculated on extract dry weight). Mikanolide, Deoxymikanolide and dihydromikanolide were active against Trypanosoma cruzi epimastigotes (50% inhibitory concentrations of 0.7, 0.08 and 2.5 mug/mL, for each compound respectively). These sesquiterpene lactones were also active against the bloodstream trypomastigotes (50% inhibitory concentrations for each compound were 2.1, 1.5 and 0.3 mug/mL, respectively) and against amastigotes (50% inhibitory concentrations for each compound were 4.5, 6.3 and 8.5 mug/mL, respectively). By contrast, scandenolide was not active on Trypanosoma cruzi. Besides, mikanolide and Deoxymikanolide were also active on Leishmania braziliensis promastigotes (50% inhibitory concentrations of 5.1 and 11.5 mug/mL, respectively). The four sesquiterpene lactones were tested for their cytotoxicity on THP 1 cells. Deoxymikanolide presented the highest selectivity index for trypomastigotes (SI = 54) and amastigotes (SI = 12.5). In an in vivo model of Trypanosoma cruzi infection, Deoxymikanolide was able to decrease the parasitemia and the weight loss associated to the acute phase of the parasite infection. More importantly, while 100% of control mice died by day 22 after receiving a lethal T. cruzi infection, 70% of Deoxymikanolide-treated mice survived. We also observed that this compound increased TNF-alpha and IL-12 production by macrophages, which could contribute to control T. cruzi infection.

Insecticidal Constituents from Buddlej aalbiflora Hemsl.[Pubmed:27764958]

Nat Prod Res. 2017 Jun;31(12):1446-1449.

Eleven known compounds, Deoxymikanolide (1), 1,3-dihydroxyxanthone (2), kumatakenin (3), apigenin (4), chrysin (5), kaempferol (6), Iso-kaempferol (7), luteolin (8), luteolin-3',4'-dimethylether-7-O-beta-glucoside (9), luteolin-7-O-beta-glucoside (10) and quercetin (11) were identified in MeOH extract of Buddleja albiflora Hemsl (Oleaceae). These compounds (each, 1, 0.5 and 0.25 mg mL(-1)) were tested for insecticidal activity against 3rd and 4th-instar larvae of Plutella xylostella, 3rd-instar larvae of Mythimna separata and 3rd-instar larvae of Macrosiphoniella sanborni. The lowest 50% anti-feedant concentration (AFC50) against P. xylostella and 50% lethal concentration (LC50) against P. xylostella and M. sanborni were observed as 0.0058, 0.0046 and 3.4048 mg L(-1), respectively.

Antimicrobial constituents of the leaves of Mikania micrantha H. B. K.[Pubmed:24098556]

PLoS One. 2013 Oct 2;8(10):e76725.

BACKGROUND: To isolate plant-derived compounds with antimicrobial activity from the leaves of Mikania micrantha, to determine the compounds configuration, and to evaluate their antimicrobial activity against eight plant pathogenic fungi (Exserohilum turcicum, Colletotrichum lagenarium, Pseudoperonispora cubensis, Botrytis cirerea, Rhizoctonia solani, Phytophthora parasitica, Fusarium solani, and Pythium aphanidermatum,) and four plant pathogenic bacteria (gram negative bacteria: Ralstonia dolaanacearum, Xanthomonas oryzae pv. Oryzae, Xanthomonas Campestris pv. Vesicatoria, and Xanthomonas campestris pv. Citri), and four bacteria (gram positive bacteria: Staphyloccocus aureus, Bacillus subtilis, Micrococcus luteus, and Bacillus cereus). METHODS AND RESULTS: Antimicrobial constituents of the leaves of M. micrantha were isolated using bioactivity- guided fractionation. The antifungal activity of the isolated compounds was evaluated by the inhibit hypha growth method and inhibit spore germination method. Characterization of antibacterial activity was carried out using the minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs). MIC and MBC were determined by the broth microdilution method. Six compounds - Deoxymikanolide, scandenolide, dihydroscandenolide, mikanolide, dihydromikanolide, and m - methoxy benzoic acid - have been isolated from leaves of Mikania micrantha H. B. K. Deoxymikanolide, scandenolide, and dihydroscandenolide were new compounds. The result of bioassay showed that all of isolated compounds were effective against tested strains and Deoxymikanolide showed the strongest activity. CONCLUSIONS AND SIGNIFICANCE: The leaves of M. micrantha may be a promising source in the search for new antimicrobial drugs due to its efficacy and the broadest range. Meanwhile, adverse impact of M. micrantha will be eliminated.

Potential allelochemicals from an invasive weed Mikania micrantha H.B.K.[Pubmed:16222800]

J Chem Ecol. 2005 Jul;31(7):1657-68.

Phytotoxicity-directed extraction and fractionation of the aerial parts of Mikania micrantha H.B.K. led to the isolation and identification of three sesquiterpenoids: dihydromikanolide, Deoxymikanolide, and 2,3-epoxy-1-hydroxy-4,9-germacradiene-12,8:15,6-diolide. These sesquiterpenoids inhibited both germination and seedling growth of tested species with Deoxymikanolide possessing the strongest phytotoxicity. In a bioassay against lettuce (Lectuca sativa L.), Deoxymikanolide reduced radicle elongation at low concentration (IC50 = 47 microg/ml); dihydromikanolide showed a weaker effect (IC50 = 96 microg/ml), and 2,3-epoxy-1-hydroxy-4,9-germacradiene-12,8:15,6-diolide exhibited the least effect (IC50 = 242 microg/ml). Deoxymikanolide caused yellowish lesions at the root tips of lettuce at a concentration of 50 microg/ml, and a 250 microg/ml solution killed lettuce seedlings. A bioassay against the monocot ryegrass (Lolium multiforum) revealed similar results on radicle elongation, which implied that the growth inhibition by these compounds was not selective. To evaluate their phytotoxicity to plants in natural habitats, three common companion tree species in south China, Acacia mangium, Eucalyptus robusta, and Pinus massoniana, were also tested and similar results were obtained. This is the first report on the isolation of 2,3-epoxy-1-hydroxy-4,9-germacradiene-12,8:15,6-diolide as a naturally occurring product.

Analgesic sesquiterpene dilactone from Mikania cordata.[Pubmed:11731117]

Fitoterapia. 2001 Dec;72(8):919-21.

The crude extract of Mikania cordata (1 and 3 g/kg, p.o.) and Deoxymikanolide (1) (10 mg/kg, p.o.) significantly inhibited acetic acid-induced writhing in mice. Three other sesquiterpene dilactones isolated from the same plant, namely mikanolide, dihydromikanolide and scandenolide, did not show significant analgesic activity.

Germacra-1,10Z,4E-dien-12,8alpha-olides from Mikania micrantha.[Pubmed:17268979]

Planta Med. 1987 Feb;53(1):105-6.

The aerial parts of MIKANIA MICRANTHA from a collection in Paraguay gave, in addition to mikanolide, Deoxymikanolide, and miscandenin, five new germacranolides all derived from 14,15-dihydroxygermacra-1(10) E,4 Z-dien-12,8alpha-olide.