Synthesis and potent antiprotozoal activity of mono/di amidino 2-anilinobenzimidazoles versus Plasmodium falciparum and Trypanosoma brucei rhodesiense

ABSTRACT A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC50) ranging from 0.12 to 10 μM, and 33 compounds active against the chloroquine- and pyrimethamine-resistant K1 strain of P. falciparum (IC50 range, 0.17 to 5 μM). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC50, 1.97 μM) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.

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Novel Azabicyclo[3.2.2]nonane derivatives and their activities against Plasmodium falciparum K1 and Trypanosoma brucei rhodesiense

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2008.05.007 ◽

2008 ◽

Vol 16 (12) ◽

pp. 6371-6378 ◽

Cited By ~ 3

Author(s):

Heinrich Berger ◽

Robert Weis ◽

Marcel Kaiser ◽

Reto Brun ◽

Robert Saf ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Trypanosoma Brucei ◽

Trypanosoma Brucei Rhodesiense

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Triterpenic Acids and Flavonoids from Satureja parvifolia. Evaluation of their Antiprotozoal Activity

Zeitschrift für Naturforschung C ◽

10.1515/znc-2006-3-406 ◽

2006 ◽

Vol 61 (3-4) ◽

pp. 189-192 ◽

Cited By ~ 25

Author(s):

Catalina van Baren ◽

Ivie Anao ◽

Paola Di Leo Lira ◽

Silvia Debenedetti ◽

Peter Houghton ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Moderate Activity ◽

Antiprotozoal Activity ◽

Active Components ◽

Trypanosoma Brucei Rhodesiense ◽

Meoh Extract ◽

Triterpenic Acids ◽

Bioassay Guided Fractionation ◽

Low Cytotoxicity ◽

First Time

Bioassay-guided fractionation of a Satureja parvifolia MeOH extract led to the isolation of eriodictyol, luteolin and ursolic and oleanolic acids as its active components against Plasmodium falciparum K1. This is the first time these compounds are reported as constituents of S. parvifolia. Ursolic acid showed an IC50 of 4.9 μg/ml, luteolin 6.4 μg/ml, oleanolic acid 9.3 μg/ml and eriodictyol 17.2 μg/ml. Antiplasmodial activity of eriodictyol and luteolin is reported here for the first time. Besides, the four compounds showed activity against P. falciparum 3D7 strain and Trypanosoma brucei rhodesiense. Eriodictyol showed moderate activity on all the parasites but was the most selective compound as a result of its rather low cytotoxicity (IC50 174.2 μg/ml) on the mammalian KB cell line.

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New 2-aminopyrimidine derivatives and their antitrypanosomal and antiplasmodial activities

Monatshefte für Chemie - Chemical Monthly ◽

10.1007/s00706-020-02674-7 ◽

2020 ◽

Vol 151 (9) ◽

pp. 1375-1385

Author(s):

Michael Hoffelner ◽

Usama Hassan ◽

Werner Seebacher ◽

Johanna Dolensky ◽

Patrick Hochegger ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Trypanosoma Brucei ◽

Phenyl Ring ◽

Ring Closure ◽

Causative Organism ◽

Amino Group ◽

Trypanosoma Brucei Rhodesiense ◽

Structural Modifications ◽

Skeletal Myoblasts

Abstract Novel 2-aminopyrimidine derivatives were prepared from acyclic starting materials, benzylidene acetones and ammonium thiocyanates, via 5 steps, including ring closure, aromatization, S-methylation, oxidation to methylsulfonyl compounds, and formation of guanidines with suitable amines. The prepared compounds differ from each other by the substitutions of their amino group and of their phenyl ring. The 2-aminopyrimidines were tested by use of microplate assays for their in vitro activities against a causative organism of sleeping sickness, Trypanosoma brucei rhodesiense, as well as against a causative organism of malaria, Plasmodium falciparum NF54. Their cytotoxic properties were determined with L-6 cells (rat skeletal myoblasts). Some of the compounds exhibited quite good antitrypanosomal activity, and others showed excellent antiplasmodial activity. The influence of the structural modifications on these activities is discussed. Graphic abstract

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Synthesis of Jacaranone-Derived Nitrogenous Cyclohexadienones and Their Antiproliferative and Antiprotozoal Activities

Molecules ◽

10.3390/molecules23112902 ◽

2018 ◽

Vol 23 (11) ◽

pp. 2902

Author(s):

Armin Presser ◽

Gunda Lainer ◽

Nadine Kretschmer ◽

Wolfgang Schuehly ◽

Robert Saf ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Physicochemical Parameters ◽

Lung Fibroblasts ◽

Antiprotozoal Activity ◽

Trypanosoma Brucei Rhodesiense ◽

L6 Cells ◽

Structure Activity ◽

Different Types ◽

Hct 116 ◽

Related Compounds

The cytotoxic and antiprotozoal activities of the phytoquinoide, jacaranone, and related compounds have been an ongoing topic in recent drug discovery. Starting from the natural product-derived cyclohexadienone scaffold, a series of nitrogen-containing derivatives were synthesized and subsequently evaluated for their antiproliferative and antiprotozoal activity. Anticancer potency was analyzed using different types of cancer cell lines: MDA-MB-231 breast cancer, CCRF-CEM leukemia, HCT-116 colon cancer, U251 glioblastoma, and, in addition, non-tumorigenic MRC-5 lung fibroblasts. Antiproliferative activities at micromolar concentrations could be shown. Antiprotozoal activity was assessed against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. For all compounds, selectivity indices (SI) were calculated based on assessed cytotoxicity towards L6 cells. In addition, the structure-activity-relationships and physicochemical parameters of these compounds are discussed.

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