scholarly journals Synthesis of 1H-3-{4-[(3-Dimethylaminopropyl)aminomethyl]phenyl}-2-phenylindole and Evaluation of Its Antiprotozoal Activity

Molbank ◽  
10.3390/m1060 ◽  
2019 ◽  
Vol 2019 (2) ◽  
pp. M1060 ◽  
Author(s):  
Jean Guillon ◽  
Clotilde Boudot ◽  
Anita Cohen ◽  
Solène Savrimoutou ◽  
Sandra Rubio ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Leishmania Donovani ◽  
Structure Characterization ◽  
Antiprotozoal Activity ◽  
Protozoan Parasites ◽  
Trypanosoma Brucei Brucei ◽  
Antiparasitic Activity ◽  
Ic50 Values

1H-3-{4-[(3-Dimethylaminopropyl)aminomethyl]phenyl}-2-phenylindole was synthesized via a multi-step pathway starting from 2-iodoaniline. Structure characterization of this new indole compound was achieved by 1H-NMR, 13C-NMR and ESI-MS spectral analysis. The title compound was screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the μM range.

scholarly journals Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

2009 ◽  
Vol 53 (9) ◽  
pp. 3815-3821 ◽  
Author(s):  
Christophe Dardonville ◽  
Cristina Fernández-Fernández ◽  
Sarah-Louise Gibbons ◽  
Nadine Jagerovic ◽  
Lidia Nieto ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Trypanosoma Cruzi ◽  
Trypanosoma Brucei ◽  
Leishmania Donovani ◽  
Antiprotozoal Activity ◽  
Protozoan Parasites ◽  
Trypanosoma Brucei Rhodesiense ◽  
Reference Drug ◽  
Axenic Amastigotes

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.

scholarly journals Synthesis and Biological Profiles of Some Benzimidazolyl-chalcones as Anti-leishmanial and Trypanocidal Agents

2021 ◽  
pp. 47-56
Author(s):  
D. U. J-P. N'Guessan ◽  
L. A. C. Kablan ◽  
A. Kacou ◽  
C. Bories ◽  
S. Coulibaly ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Leishmania Donovani ◽  
Parasite Growth ◽  
Drug Candidate ◽  
Trypanosoma Brucei Brucei ◽  
Reference Drug ◽  
Starting Point ◽  
Ic50 Values ◽  
Chlorine Derivative

Background: Benzimidazole constitutes a starting point for the development of new antiprotozoal agents since this nucleus exists in several pharmacologically significant molecules, in particular possessing antifungal, antiviral, antibacterial, and antiparasitic properties. Objective: The present study aimed to identify a molecular hit likely to be developed as an anti-leishmanial and antitrypanosomal drug candidate. Methods: Thus, 12 hybrids of chalcone or benzimidazolyl-arylpropenones were synthesized and screened in vitro for anti-leishmanial activity against promastigotes of Leishmania donovani. The microculture tetrazolium assay was used to determine their potential to inhibit 50% of a parasite growth (IC50). Results: Two compounds among 5-chlorobenzimidazole-chalcones (4a and 4c), which exhibited potent activity (IC50<1 μM) against L. donovani and one derivative (4d) poorly effective against L. donovani (IC50>50 μM) were selected to check their trypanocidal activity. Lethal concentration (LC100) values of these compounds were estimated by using observations on the viability of trypomastigotes of Trypanosoma brucei brucei in MEM medium with Earle’s salts and L-glutamine. Seven of the tested compounds (4a, 4b, 4c, 4e, 4g, 4h, and 4j) showed particularly higher inhibitory activity than pentamidine (IC50= 7.6 μM) against L. donovani promastigotes with IC50 values in a range from 0.5 to 1.8 μM. In addition, the 2’-chlorine derivative (4c), displayed potent anti-trypanosomal activity comparable to those of melarsoprol, used as reference drug. Conclusion: These results support this series of benzimidazole holding arylpropenone group in position 2 as a starting point for future optimization to get novel agents active against leishmaniasis and trypanosomiasis.

scholarly journals Characterization of Trypanosoma brucei bruceiS-adenosyl-l-methionine decarboxylase and its inhibition by Berenil, pentamidine and methylglyoxal bis(guanylhydrazone)

1986 ◽  
Vol 237 (3) ◽  
pp. 685-689 ◽  
Author(s):  
A J Bitonti ◽  
J A Dumont ◽  
P P McCann
Keyword(s):  
Trypanosoma Brucei ◽  
Decarboxylase Activity ◽  
Inhibitory Effects ◽  
Trypanosoma Brucei Brucei ◽  
Curative Effect ◽  
Model Mouse ◽  
Mammalian Enzyme

Trypanosoma brucei brucei S-adenosyl-L-methionine (AdoMet) decarboxylase was found to be relatively insensitive to activation by putrescine as compared with the mammalian enzyme, being stimulated by only 50% over a 10,000-fold range of putrescine concentrations. The enzyme was not stimulated by up to 10 mM-Mg2+. The Km for AdoMet was 30 microM, similar to that of other eukaryotic AdoMet decarboxylases. T.b. brucei AdoMet decarboxylase activity was apparently irreversibly inhibited in vitro by Berenil and reversibly by pentamidine and methylglyoxal bis(guanylhydrazone). Berenil also inhibited trypanosomal AdoMet decarboxylase by 70% within 4 h after administration to infected rats and markedly increased the concentration of putrescine in trypanosomes that were exposed to the drug in vivo. Spermidine and spermine blocked the curative effect of Berenil on model mouse T.b. brucei infections. This effect of the polyamines was probably not due to reversal of Berenil's inhibitory effects on the AdoMet decarboxylase.

scholarly journals Biological and Phytochemical Investigations on Caesalpinia benthamiana, a Plant Traditionally Used as Antimalarial in Guinea

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Jean Loua ◽  
Mohamed Sahar Traore ◽  
Aissata Camara ◽  
Mamadou Aliou Balde ◽  
Louis Maes ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Methanolic Extract ◽  
Moderate Activity ◽  
Good Activity ◽  
Phytochemical Screening ◽  
Antiprotozoal Activity ◽  
Trypanosoma Brucei Brucei ◽  
Leaf Extracts ◽  
Bioassay Guided Fractionation

Caesalpinia benthamiana is widely used as antimalarial in Guinean traditional medicine. Leaf extracts of the plant were tested for their in vitro antiprotozoal activity against Trypanosoma brucei brucei and T. cruzi and the chloroquine-sensitive Ghana strain of Plasmodium falciparum along with their cytotoxicity on MRC-5 cells. The methanolic extract showed the strongest antiprotozoal activity against P. falciparum (IC50 4 μg/ml), a good activity against T. brucei (IC50 13 μg/ml), and a moderate activity against T. cruzi (IC50 31 μg/ml) along with an IC50 on human MRC-5 cells of 32 μg/ml. Bioassay-guided fractionation from the methanolic extract led to antiplasmodially active subfractions. A prospective, placebo-controlled ethnotherapeutic trial assessed the antimalarial effectiveness and tolerability of C. benthamiana syrup administered orally to children with uncomplicated malaria as compared with chloroquine syrup. Phytochemical screening of the leaf extracts indicated the presence of flavonoids, terpenoids, tannins, saponins, and iridoids.

scholarly journals Synthesis, Structure and In Vitro Anti-Trypanosomal Activity of Non-Toxic Arylpyrrole-Based Chalcone Derivatives

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1668
Author(s):  
Ayanda I. Zulu ◽  
Ogunyemi O. Oderinlo ◽  
Cuan Kruger ◽  
Michelle Isaacs ◽  
Heinrich C. Hoppe ◽  
...  
Keyword(s):  
Hela Cell ◽  
Cell Line ◽  
Trypanosoma Brucei ◽  
Hela Cell Line ◽  
Trypanosoma Brucei Brucei ◽  
Chalcone Derivatives ◽  
Ic50 Values ◽  
Potential Activity ◽  
Human Cervix

With an intention of identifying chalcone derivatives exhibiting anti-protozoal activity, a cohort of relatively unexplored arylpyrrole-based chalcone derivatives were synthesized in moderate to good yields. The resultant compounds were evaluated in vitro for their potential activity against a cultured Trypanosoma brucei brucei 427 strain. Several compounds displayed mostly modest in vitro anti-trypanosomal activity with compounds 10e and 10h emerging as active candidates with IC50 values of 4.09 and 5.11 µM, respectively. More importantly, a concomitant assessment of their activity against a human cervix adenocarcinoma (HeLa) cell line revealed that these compounds are non-toxic.

scholarly journals Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4204
Author(s):  
George E. Magoulas ◽  
Pantelis Afroudakis ◽  
Kalliopi Georgikopoulou ◽  
Marina Roussaki ◽  
Chiara Borsari ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Developmental Stages ◽  
Neglected Tropical Diseases ◽  
Heterocyclic Ring ◽  
Head Group ◽  
Ether Phospholipid ◽  
Design Synthesis ◽  
Antiparasitic Activity ◽  
Intracellular Amastigotes

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure–activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) against THP-1 macrophages ranged between 50 and 100 μM. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases.

scholarly journals Easy-To-Access Quinolone Derivatives Exhibiting Antibacterial and Anti-Parasitic Activities

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1141
Author(s):  
Richard M. Beteck ◽  
Audrey Jordaan ◽  
Ronnett Seldon ◽  
Dustin Laming ◽  
Heinrich C. Hoppe ◽  
...  
Keyword(s):  
Cell Wall ◽  
Protozoan Parasites ◽  
Trypanosoma Brucei Brucei ◽  
New Class ◽  
High Lipid ◽  
Host Infection ◽  
Eskape Pathogens ◽  
Quinolone Derivatives ◽  
Lipophilic Character

The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC90 values in the range of 0.24–31 µM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4–20 µM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.

scholarly journals Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major

2006 ◽  
Vol 396 (2) ◽  
pp. 277-285 ◽  
Author(s):  
Chrysoula Panethymitaki ◽  
Paul W. Bowyer ◽  
Helen P. Price ◽  
Robin J. Leatherbarrow ◽  
Katherine A. Brown ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Leishmania Major ◽  
Homo Sapiens ◽  
Selective Inhibition ◽  
Fungal Species ◽  
Chemotherapeutic Agents ◽  
Human Pathogens ◽  
Ic50 Values

The eukaryotic enzyme NMT (myristoyl-CoA:protein N-myristoyltransferase) has been characterized in a range of species from Saccharomyces cerevisiae to Homo sapiens. NMT is essential for viability in a number of human pathogens, including the fungi Candida albicans and Cryptococcus neoformans, and the parasitic protozoa Leishmania major and Trypanosoma brucei. We have purified the Leishmania and T. brucei NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and specific peptide substrates. A number of inhibitory compounds that target NMT in fungal species have been tested against the parasite enzymes in vitro and against live parasites in vivo. Two of these compounds inhibit TbNMT with IC50 values of <1 μM and are also active against mammalian parasite stages, with ED50 (the effective dose that allows 50% cell growth) values of 16–66 μM and low toxicity to murine macrophages. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against infectious diseases including African sleeping sickness and Nagana.

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