Plant-derived alkaloids active against Trypanosoma cruzi

doi:10.1016/0378-8741(87)90140-1

Journal of Ethnopharmacology

Volume 19, Issue 1, January–February 1987, Pages 89-94

https://doi.org/10.1016/0378-8741(87)90140-1 Get rights and content

Abstract

Six plant-derived simple β-carboline alkaloids and eight other plant derivatives were tested for activity against the protozoan parasite, Trypanosoma cruzi, the organism responsible for Chagas' disease. The plant alkaloids in this study were screened using an in vitro test against epimastigotes. Four β-carboline indoles, a complex indole and five other alkaloids significantly reduced population growth of T. cruzi (Costa Rica strain) epimastigote forms at a concentration of 50 μg/ml or less.

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Cited by (30)

Promising trypanocidal heterocyclic compounds of natural origin and their synthetic analogs
2019, Discovery and Development of Therapeutics from Natural Products Against Neglected Tropical Diseases
Diseases caused by members of the order Trypanosomatidae include human African trypanosomiasis (HAT) and Chagas disease, caused by species of Trypanosoma brucei and Trypanosoma cruzi, respectively, as well as leishmaniasis, caused by various species of Leishmania spp. These infections belong to the so-called neglected tropical diseases group, which are a diverse group of communicable diseases that prevail in tropical and subtropical conditions in 149 countries and affect more than one billion people in addition to costing developing economies billions of dollars every year. The available pharmacotherapies for combatting these diseases are limited and associated with strong side effects, and moreover, resistances have developed against most drugs. The urgent need for new drugs against these infections has guided the search for natural products stemming from traditional medicines which historically have been used as therapeutic agents, especially in developing countries. Thus in the past decade, a huge number of trypanocidal natural compounds have been isolated and characterized. This chapter summarizes the most significant topics concerning current therapy of trypanosomiasis (Chagas disease and HAT) and presents the compound classes and chemical entities which have been identified by bioactivity-guided fractionation of active herbal or microbial extracts. The chapter mainly focuses on promising natural or semisynthetic heterocyclic compounds. Their biological activities, antiparasitic activities, and cytotoxicities are discussed here. In the few cases where their mechanisms of action have been studied in detail, the activities of the target enzymes are also given.
Antitrypanosomal and antileishmanial activities of novel N-alkyl-(1-phenylsubstituted-β-carboline)-3-carboxamides
2010, Biomedicine and Pharmacotherapy
A series of 1-phenylsubstituted β-carbolines containing an N-butylcarboxamide group at C-3 of β-carboline nucleus were synthesized and evaluated in vitro against epimastigote form of Trypanosoma cruzi and promastigote form of Leishmania amazonensis. Among all compounds tested, two derivatives (2b and 2d) presented potent activity against both parasites. The most active derivative 2b showed also the higher selectivity index ratio (SI) for L. amazonensis (SI = 2,084). The effect of other N-alkylcarboxamide groups at C-3, such as pyrrolidyl, N-cyclohexil and N-benzylcarboxamide on T. cruzi and L. amazonensis activity was also evaluated. Our results pointed the synthesized β-carboline-3-carboxamide derivatives as potential compounds for new drugs for Chagas’ disease and leishmaniasis’ treatment.
Biological activity of 1,2,3,4-tetrahydro-β-carboline-3-carboxamides against Trypanosoma cruzi
2009, Acta Tropica
Citation Excerpt :
Natural and synthetic β-carbolines and tetrahydro-β-carboline alkaloids are well-known compounds that possess several biological properties, such as anticonvulsive, ansiolytic, sedative, antimicrobial, antithrombotic, anti-HIV, antiproliferative, insecticidal, and parasiticidal (Ishida et al., 2001; Lin et al., 2002; Castro et al., 2003; Takasu et al., 2004; Cao et al., 2005; Costa et al., 2006). This class of compounds has been tested in trypanocidal assays, and some reports have shown the activity of β-carbolines and tetrahydro-β-carbolines against T. cruzi (Calvin et al., 1987). In a previous work we demonstrated the activity of 1-(nitrophenyl)-tetrahydro-β-carbolines against epimastigote forms of T. cruzi (Tonin et al., 2008).
Several β-carboline compounds were evaluated for in vitro trypanocidal activity against Trypanosoma cruzi and their potential toxic effects was also assessed. β-Carboline derivative 4 showed good activity against epimastigote, trypomastigote, and amastigote forms of T. cruzi, with a dose-dependent inhibitory effect. It showed an IC₅₀ of 14.9 μM against the epimastigote form and an EC₅₀ of 45 μM and 33 μM against trypomastigote and amastigote forms, respectively. Additionally, 4 was able to be active on mammalian cell–protozoan interaction, reducing the number of infected cells and the number of internalized parasites. The compound showed low cytotoxicity, with a selective index 31 times higher to the parasite than for mammalian cells. In human red-blood cells β-Carboline 4 at 14.9 μM not caused haemolysis. Observed at electron microscopy 4-treated epimastigotes showed abnormal swelling of the mitochondrion, a diffuse kinetoplast, and distortions of the parasite cell body. The present data support the potential effect of this class of compounds against T. cruzi and encourage further experiments in vitro to evaluate the action mechanism of this drug and also with in vivo models.
Comparative study of the trypanocidal activity of the methyl 1-nitrophenyl-1,2,3,4-9H-tetrahydro-β-carboline-3-carboxylate derivatives and benznidazole using theoretical calculations and cyclic voltammetry
2009, European Journal of Medicinal Chemistry
Citation Excerpt :
Natural and synthetic β-carbolines and tetrahydro-β-carbolines alkaloids are well-known compounds that possess a variety of biological properties, such as anticonvulsive, ansiolytic, sedative, antimicrobial, antithrombotic, anti-HIV, antiproliferative, insecticidal, and parasiticidal [4–6]. In the recent years, this class of compounds has been tested in trypanocidal assays against T. cruzi [7–9]. The importance of the search for new effective chemotherapy agents for the treatment of Chagas disease together with the trypanocidal activity reported for tetrahydro-β-carboline alkaloids, lead us to study this class of compounds.
The cis and trans isomers of methyl 1-(m-nitro)phenyl and 1-(p-nitro)phenyl-1,2,3,4-tetrahydro-9H-β-carboline-3-carboxylates (compounds 3a,b, 4a and b) were synthesized and evaluated in vitro against epimastigote forms of Trypanosoma cruzi. Among all of the evaluated tetrahydro-β-carboline derivatives, the compound trans-methyl 1-(m-nitro)phenyl-1,2,3,4-9H-tetrahydro-β-carboline-3-carboxylate (3b) was found to exhibit significant trypanocidal activity (IC₅₀ = 22.2 μM). Theoretical studies of molecular conformations and electronic properties for the synthesized compounds and benznidazole, as well as, the cyclic voltammetric (CV) behaviors' determination were performed. A comparative study of the trypanocidal activity of the nitrophenyl-tetrahydro-β-carbolines derivatives and benznidazole, using the results of theoretical calculations and of the cyclic voltammetry experiments, is presented.
The use of natural product scaffolds as leads in the search for trypanothione reductase inhibitors
2008, Bioorganic and Medicinal Chemistry
Twenty-three heterocyclic compounds were evaluated for their potential as trypanothione reductase inhibitors. As a result, the harmaline, 10-thiaisoalloxazine, and aspidospermine frameworks were identified as the basis of inhibitors of Trypanosoma cruzi trypanothione reductase. Two new compounds showed moderately strong, linear competitive inhibition, namely N,N-dimethyl-N-[3-(7-methoxy-1-methyl-3,4-dihydro-9H-β-carbolin-9-yl)propyl]amine (15) and 1,3-bis[3-(dimethylamino)propyl]-1,5-dihydro-2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione (21), with K_i values of 35.1 ± 3.5 μM and 26.9 ± 1.9 μM, respectively. Aspidospermine (25) inhibited T. cruzi TryR with a K_i of 64.6 ± 6.2 μM. None of the compounds inhibited glutathione reductase. Their toxicity toward promastigotes of Leishmania amazonensis was assessed.
Chapter 2 Alkaloids with Antiprotozoal Activity
2008, Alkaloids: Chemistry and Biology
Citation Excerpt :
A fully unsaturated pyridoindole ring system seems to be a necessary condition for optimal activity in these compounds. This could be associated with planarity of the molecule, its redox behavior or its electron density distribution, to mention three possible structural desiderata (254,256). Nevertheless, other mechanisms could be involved, since compounds such as harmaline (162), a dihydro-β-carboline, present greater antiprotozoal activity than fully aromatic compounds.
This chapter discusses the alkaloid natural products that are particularly active against Leishmania sp., Trypanosomacruzi, Trypanosomabrucei, and Plasmodium falciparum. The alkaloids with antiprotozoal activity are grouped according to their structures or origin in several categories such as quinoline and isoquinoline alkaloids, indole alkaloids, steroidal alkaloids, alkaloids from marine organisms, and other alkaloids. A discussion on structure-antiprotozoal activity relationships is included, and the mechanism of action of several of these metabolites is described in the chapter. Recent developments, as well as new experimental strategies in discovery and development of antiprotozoal compounds, are also discussed in the chapter. Some of the in vitro antitrypanosomal or cytotoxic activities have been transformed into molar concentrations to allow a better comparison, independent of their molecular weight. Nevertheless, direct comparison remains complex because of the different assay procedures used in various laboratories. Alkaloids are one of the most important groups of natural products, already providing many drugs for human use. Although they can be seriously toxic for the host, alkaloid-containing plants and their biosynthesized alkaloids have a remarkable potential to provide pharmaceutical and biological agents contributing to the development of future antiparasitic drugs. Natural alkaloids will continue to play an important role in the development of a new generation of antiprotozoal drugs.

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Journal of Ethnopharmacology

Abstract

References (23)

The simple β-carboline alkaloids

Phytochemistry

Harmine tremor after brain monoamine oxidase inhibition in the mouse

European Journal of Pharmacology

Studies of the interaction of the flurophores harmine and harmaline with calf thymus DNA

Biochimica et Biophysica Acta

Ultra-violet mediated cytotoxic activity of β-carboline alkaloids

Phytochemistry

The possible role of amazonian psychoactive plants in the chemotherapy of parasitic worms—A hypothesis

Journal of Ethnopharmacology

Effects of DAPI, a new diamidine trypanocide, on the ultrastructure of Trypanosoma rhodesiense

Transactions of the Royal Society of Tropical Medicine and Hygiene

Ethnopharmacognosy of amazonian psychoactive plants

Effects of harman and norharman on spontaneous and ultraviolet light-induced mutagenesis in cultured Chinese hamster cells

Cancer Research

The effects of harmaline on sodium transport in human erythrocytes

Journal of Pharmacology and Experimental Therapeutics

Comparative drug sensitivities of culture forms of Trypanosoma cruzi and Trypanosoma dionisii

Nature (Lond.)

Cited by (30)

Promising trypanocidal heterocyclic compounds of natural origin and their synthetic analogs

Antitrypanosomal and antileishmanial activities of novel N-alkyl-(1-phenylsubstituted-β-carboline)-3-carboxamides

Biological activity of 1,2,3,4-tetrahydro-β-carboline-3-carboxamides against Trypanosoma cruzi

Comparative study of the trypanocidal activity of the methyl 1-nitrophenyl-1,2,3,4-9H-tetrahydro-β-carboline-3-carboxylate derivatives and benznidazole using theoretical calculations and cyclic voltammetry

The use of natural product scaffolds as leads in the search for trypanothione reductase inhibitors

Chapter 2 Alkaloids with Antiprotozoal Activity