Trypanocidal and Leishmanicidal Properties of Substitution-Containing Chalcones

ABSTRACT Ten chalcones were synthesized and tested as potential leishmanicidal and trypanocidal agents. All tested compounds caused concentration-dependent inhibition of the in vitro growth of Leishmania braziliensis and Trypanosoma cruzi with no significant toxic effect towards host macrophages. Our results show that the positions of the substituents seem to be critical for their antiprotozoal activities.

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Lipid biosynthesis pathways as chemotherapeutic targets in kinetoplastid parasites

Parasitology ◽

10.1017/s0031182097001194 ◽

1997 ◽

Vol 114 (7) ◽

pp. 91-99 ◽

Cited By ~ 134

Author(s):

J. A. URBINA

Keyword(s):

Trypanosoma Cruzi ◽

Recent Work ◽

Chagas Disease ◽

Pneumocystis Carinii ◽

Lipid Biosynthesis ◽

Sterol Biosynthesis ◽

Leishmania Braziliensis ◽

Biosynthesis Inhibitors

Inhibitors of sterol and phospholipid biosynthesis in kinetoplastid parasites such as Trypanosoma cruzi, the causative agent of Chagas' disease, and different species of Leishmania have potent and selective activity as chemotherapeutic agents in vitro and in vivo. Recent work with the sterol C14α-demethylase inhibitor D0870, a bis triazole derivative, showed that this compound is capable of inducing radical parasitological cure in murine models of both acute and chronic Chagas' disease. Other inhibitors of this type, such as SCH 56592, have also shown curative, rather than suppressive, activity against T. cruzi in these models. Leishmania species have different susceptibilities to sterol biosynthesis inhibitors, both in vitro and in vivo. Leishmania braziliensis promastigotes, naturally resistant to C14α-demethylase inhibitors such as ketoconazole and D0870, were susceptible to these drugs when used in combination with the squalene epoxidase inhibitor terbinafine. Inhibitors of Δ24(25) sterol methyl transferase have been shown to act as potent antiproliferative agents against Trypanosoma cruzi, both in vitro and in vivo. New inhibitors of this type which show enhanced activity and novel mechanisms of action have been synthesized. Recent work has also demonstrated that this type of enzyme inhibitors can block sterol biosynthesis and cell proliferation in Pneumocystis carinii, a fungal pathogen which had previously been found resistant to other sterol biosynthesis inhibitors. Ajoene, an antiplatelet compound derived from garlic, was shown to have potent antiproliferative activity against epimastigotes and amastigotes of Trypanosoma cruzi in vitro; this activity was associated with a significant alteration of the phospholipid composition of the cells with no significant effects on the sterol content. In addition, alkyllsophospholipids such as ilmofosine, miltefosine and edelfosine have been shown to block the proliferation of T. cruzi and Leishmania and alter both the phospholipid and sterol composition. These results indicate the potential of lipid biosynthesis inhibitors as useful therapeutic agents in the treatment of leishmaniasis and Chagas' disease.

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Toxic effect of isolated glycophorin a on the in vitro growth of Plasmodium falciparum

Blut Zeitschrift für die gesamte Blutforschung ◽

10.1007/bf00321041 ◽

1987 ◽

Vol 54 (2) ◽

pp. 115-122 ◽

Cited By ~ 6

Author(s):

P. Hermentin ◽

G. Neunziger ◽

B. Enders ◽

W. Dahr

Keyword(s):

Plasmodium Falciparum ◽

Toxic Effect ◽

Glycophorin A ◽

In Vitro Growth

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The effect of adenosine analogues on the in vitro growth of Trypanosoma cruzi

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1016/0035-9203(82)90169-9 ◽

1982 ◽

Vol 76 (3) ◽

pp. 285-287 ◽

Cited By ~ 9

Author(s):

Jeffrey P. Nadler ◽

Edgar Lederer ◽

Murray Wittner ◽

Stephen G. Baum ◽

Herbert B. Tanowitz

Keyword(s):

Trypanosoma Cruzi ◽

In Vitro Growth ◽

Adenosine Analogues

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The Effect of Peritoneal Macrophages from Mice Injected with Leishmania Braziliensis on the in Vitro Growth of Tumor Cells

Immunological Communications ◽

10.3109/08820137909050059 ◽

1979 ◽

Vol 8 (4) ◽

pp. 457-468

Author(s):

Fernando Merino ◽

Juan Luis

Keyword(s):

Tumor Cells ◽

Peritoneal Macrophages ◽

Leishmania Braziliensis ◽

In Vitro Growth ◽

Growth Of Tumor

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SARs for the Antiparasitic Plant Metabolite Pulchrol. Part 2: B- and C-Ring Substituents

Molecules ◽

10.3390/molecules25194510 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4510

Author(s):

Paola Terrazas ◽

Sophie Manner ◽

Olov Sterner ◽

Marcelo Dávila ◽

Alberto Giménez ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Neglected Tropical Diseases ◽

Leishmania Species ◽

Positive Control ◽

Leishmania Braziliensis ◽

General Tendency ◽

Antiparasitic Activity ◽

Plant Metabolite ◽

Derivatives Of

Neglected tropical diseases affect most of the underprivileged populations in tropical countries. Among these are chagas and leishmaniasis, present mainly in South and Central America, Africa and East Asia. Current treatments are long and have severe adverse effects, therefore there is a strong need to develop alternatives. In this study, we base our research on the plant metabolite pulchrol, a natural benzochromene which has been shown to possess antiparasitic activity against Trypanosoma and Leishmania species. In a recent study, we investigated how changes in the benzyl alcohol functionality affected the antiparasitic activity, but the importance of B- and C-ring substituents is not understood. Fifteen derivatives of pulchrol with different substituents in positions 1, 2, 3, and 6 while leaving the A-ring intact, were therefore prepared by total synthesis, assayed, and compared with pulchrol and positive controls. The generated series and parental molecule were tested in vitro for antiparasitic activity against Trypanosoma cruzi, Leishmania braziliensis, and L. amazonensis, and cytotoxicity using RAW cells. Substantial differences in the activity of the compounds synthesized were observed, of which some were more potent towards Trypanosoma cruzi than the positive control benznidazole. A general tendency is that alkyl substituents improve the potency, especially when positioned on C-2.

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Human urine stimulates in vitro growth of Trypanosoma cruzi and Trypanosoma rangeli

Parasitology Research ◽

10.1007/s00436-007-0654-0 ◽

2007 ◽

Vol 101 (5) ◽

pp. 1383-1388 ◽

Cited By ~ 11

Author(s):

Keila A. M. Ferreira ◽

Paulo E. S. Lemos-Júnior ◽

Eliane Lages-Silva ◽

Luis E. Ramírez ◽

André L. Pedrosa

Keyword(s):

Trypanosoma Cruzi ◽

Human Urine ◽

In Vitro Growth ◽

Trypanosoma Rangeli

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Artemisinins Inhibit Trypanosoma cruzi and Trypanosoma brucei rhodesiense In Vitro Growth

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01544-06 ◽

2007 ◽

Vol 51 (5) ◽

pp. 1852-1854 ◽

Cited By ~ 85

Author(s):

Yuliya V. Mishina ◽

Sanjeev Krishna ◽

Richard K. Haynes ◽

John C. Meade

Keyword(s):

Trypanosoma Cruzi ◽

Atpase Activity ◽

Trypanosoma Brucei ◽

Mode Of Action ◽

In Vitro Growth ◽

Trypanosoma Brucei Rhodesiense ◽

Calcium Dependent ◽

Membrane Pumps ◽

Micromolar Range

ABSTRACT Artemisinin compounds inhibit in vitro growth of cultured Trypanosoma cruzi and Trypanosoma brucei rhodesiense at concentrations in the low micromolar range. Artemisinin also inhibits calcium-dependent ATPase activity in T. cruzi membranes, suggesting a mode of action via membrane pumps. Artemisinins merit further investigation as chemotherapeutic options for these pathogens.

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SARs for the Antiparasitic Plant Metabolite Pulchrol. 3. Combinations of New Substituents in A/B-Rings and A/C-Rings

Molecules ◽

10.3390/molecules26133944 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3944

Author(s):

Paola Terrazas ◽

Efrain Salamanca ◽

Marcelo Dávila ◽

Sophie Manner ◽

Alberto Gimenez ◽

...

Keyword(s):

Natural Products ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Binding Sites ◽

Hydroxyl Group ◽

Neglected Diseases ◽

Leishmania Braziliensis ◽

Antiparasitic Activity ◽

Plant Metabolite

The natural products pulchrol and pulchral, isolated from the roots of the Mexican plant Bourreria pulchra, have previously been shown to possess antiparasitic activity towards Trypanosoma cruzi, Leishmania braziliensis and L. amazonensis, which are protozoa responsible for Chagas disease and leishmaniasis. These infections have been classified as neglected diseases, and still require the development of safer and more efficient alternatives to their current treatments. Recent SARs studies, based on the pulchrol scaffold, showed which effects exchanges of its substituents have on the antileishmanial and antitrypanosomal activity. Many of the analogues prepared were shown to be more potent than pulchrol and the current drugs used to treat leishmaniasis and Chagas disease (miltefosine and benznidazole, respectively), in vitro. Moreover, indications of some of the possible interactions that may take place in the binding sites were also identified. In this study, 12 analogues with modifications at two or three different positions in two of the three rings were prepared by synthetic and semi-synthetic procedures. The molecules were assayed in vitro towards T. cruzi epimastigotes, L. braziliensis promastigotes, and L. amazonensis promastigotes. Some compounds had higher antiparasitic activity than the parental compound pulchrol, and in some cases even benznidazole and miltefosine. The best combinations in this subset are with carbonyl functionalities in the A-ring and isopropyl groups in the C-ring, as well as with alkyl substituents in both the A- and C-rings combined with a hydroxyl group in position 1 (C-ring). The latter corresponds to cannabinol, which indeed was shown to be potent towards all the parasites.

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