In Silico Study of Structural and Geometrical Requirements of Natural Sesquiterpene Lactones with Trypanocidal Activity

Fabián, Lucas; Sülsen, Valeria P.; Frank, Fernanda M.; Cazorla, Silvia I.; Malchiodi, Emilio L.; Martino, Virginia; Lizarraga, Emilio Fernando; Catalán, César A.N.; Moglioni, Albertina G.; Muschietti, Liliana; Finkielsztein, Liliana M.

doi:10.2174/13895575113139990066

Cited by 16 publications

(14 citation statements)

References 25 publications

(30 reference statements)

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“…A strong correlation between biological activity and cytotoxicity of STLs has been reported [ 29 ]. Although many of them display a considerable cytotoxic activity against mammalian cells, some of these compounds show more selectivity against the parasites [ 31 ]. Deoxymikanolide presented a CC 50 that was approximately four times higher than mikanolide, thus proving to be more selective for the parasite.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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 μg/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 μg/mL, respectively) and against amastigotes (50% inhibitory concentrations for each compound were 4.5, 6.3 and 8.5 μg/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 μg/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-α and IL-12 production by macrophages, which could contribute to control T. cruzi infection.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Sesquiterpenic lactones are molecules of natural origin which are emerging as promising source of bioactive prototype molecules with potential activity against Trypanosoma cruzi 20,21 . Treatment with LYC in PLA-PEG NC in acute and chronic phases of the infection has produced potent anti-trypanosomal efficacy in a mice model and may represent a valuable alternative to reference drugs benznidazole and nifurtimox, in particular in the case of T. cruzi strains resistant to these drugs 12,22 .…”

Section: Discussionmentioning

confidence: 99%

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

Farah¹,

Branquinho²,

Roy³

et al. 2017

Archives of Cardiovascular Diseases Supplements

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Chagas disease is a neglected parasitic disease caused by the protozoan Trypanosoma cruzi. New antitrypanosomal options are desirable to prevent complications, including a high rate of cardiomyopathy. Recently, a natural substance, lychnopholide, has shown therapeutic potential, especially when encapsulated in biodegradable polymeric nanocapsules. However, little is known regarding possible adverse effects of lychnopholide. Here we show that repeated-dose intravenous administration of free lychnopholide (2.0 mg/kg/day) for 20 days caused cardiopathy and mortality in healthy C57BL/6 mice. Echocardiography revealed concentric left ventricular hypertrophy with preserved ejection fraction, diastolic dysfunction and chamber dilatation at end-stage. Single cardiomyocytes presented altered contractility and Ca 2+ handling, with spontaneous Ca 2+ waves in diastole. Acute in vitro lychnopholide application on cardiomyocytes from healthy mice also induced Ca 2+ handling alterations with abnormal RyR2-mediated diastolic Ca 2+ release. Strikingly, the encapsulation of lychnopholide prevented the cardiac alterations induced in vivo by the free form repeated doses. Nanocapsules alone had no adverse cardiac effects. Altogether, our data establish lychnopholide presented in nanocapsule form more firmly as a promising new drug candidate to cure Chagas disease with minimal cardiotoxicity. Our study also highlights the potential of nanotechnology not only to improve the efficacy of a drug but also to protect against its adverse effects. Chagas disease (CD) is an important neglected disease caused by an intracellular hemoflagellate protozoan parasite, Trypanosoma cruzi (T. cruzi).There are an estimated 6-7 million infected people worldwide, and the disease causes 12 500 deaths per year, mostly in Latin America (World Health Organization, Switzerland 2015). While CD is principally transmitted to humans by triatomine insects, other routes include blood transfusion or transplantation of contaminated organs, ingestion of contaminated food and congenital transmission from infected mothers to newborns. International migrations contribute to spread the disease in non-endemic areas such as North America, Europe and Western Pacific countries (World Health Organization, Switzerland 2015). CD evolves in different consecutive phases with a short acute period, characterized by patent parasitemia, followed by a chronic phase in which most infected individuals remain asymptomatic (indeterminate form). CD is also a common determinant of non-ischemic cardiomyopathy in addition to digestive complications and neurological disorders. Approximately 30% of patients infected with T. cruzi manifest cardiomyopathy characterized by severe myocarditis and multiple arrhythmias, and/or dilatation and physiological dysfunctions of hollow organs, mainly of the digestive tract, which develop progressively over the years or decades after infection [1][2][3][4] . The clinical course of CD shows great variability, and the mechanisms or determinants responsible for t...

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“…Cross-validation coefficient values are not reported. The authors found that a correlation of the observed antitrypanosomal activity existed with the steric parameters of the set of molecules tested and concluded that SLs have a high potential as lead molecules against Chagas disease [ 92 ].…”

Section: Cadd Studies Against Ntdsmentioning

confidence: 99%

Computer-Aided Drug Design Using Sesquiterpene Lactones as Sources of New Structures with Potential Activity against Infectious Neglected Diseases

et al. 2017

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This review presents an survey to the biological importance of sesquiterpene lactones (SLs) in the fight against four infectious neglected tropical diseases (NTDs)—leishmaniasis, schistosomiasis, Chagas disease, and sleeping sickness—as alternatives to the current chemotherapies that display several problems such as low effectiveness, resistance, and high toxicity. Several studies have demonstrated the great potential of some SLs as therapeutic agents for these NTDs and the relationship between the protozoal activities with their chemical structure. Recently, Computer-Aided Drug Design (CADD) studies have helped increase the knowledge of SLs regarding their mechanisms, the discovery of new lead molecules, the identification of pharmacophore groups and increase the biological activity by employing in silico tools such as molecular docking, virtual screening and Quantitative-Structure Activity Relationship (QSAR) studies.

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In Silico Study of Structural and Geometrical Requirements of Natural Sesquiterpene Lactones with Trypanocidal Activity

Cited by 16 publications

References 25 publications

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

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

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

Computer-Aided Drug Design Using Sesquiterpene Lactones as Sources of New Structures with Potential Activity against Infectious Neglected Diseases

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