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

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.

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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 ◽

Cited By ~ 2

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.

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Isothiochromenothiazoles—A Class of Fused Thiazolidinone Derivatives with Established Anticancer Activity That Inhibits Growth of Trypanosoma brucei brucei

Scientia Pharmaceutica ◽

10.3390/scipharm86040047 ◽

2018 ◽

Vol 86 (4) ◽

pp. 47 ◽

Cited By ~ 4

Author(s):

Anna Kryshchyshyn ◽

Danylo Kaminskyy ◽

Igor Nektegayev ◽

Philippe Grellier ◽

Roman Lesyk

Keyword(s):

Acute Toxicity ◽

Anticancer Activity ◽

Trypanosoma Brucei ◽

In Vitro Assay ◽

Parasite Growth ◽

Trypanosoma Brucei Brucei ◽

Vitro Assay ◽

Antiparasitic Agents ◽

Micromolar Range

Recently, thiazolidinone derivatives have been widely studied as antiparasitic agents. Previous investigations showed that fused 4-thiazolidinone derivatives (especially thiopyranothiazoles) retain pharmacological activity of their synthetic precursors—simple 5-ene-4-thiazolidinones. A series of isothiochromeno[4a,4-d][1,3] thiazoles was investigated in an in vitro assay towards bloodstream forms of Trypanosoma brucei brucei. All compounds inhibited parasite growth at concentrations in the micromolar range. The established low acute toxicity of this class of compounds along with a good trypanocidal profile indicates that isothiochromenothiazole derivatives may be promising for designing new antitrypanosomal drugs.

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Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00124-09 ◽

2009 ◽

Vol 53 (9) ◽

pp. 3815-3821 ◽

Cited By ~ 10

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.

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

Molecules ◽

10.3390/molecules25071668 ◽

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.

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In vitro Activity of Diospyrin and Derivatives against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei brucei

Phytotherapy Research ◽

10.1002/(sici)1099-1573(199611)10:7<559::aid-ptr891>3.0.co;2-v ◽

1996 ◽

Vol 10 (7) ◽

pp. 559-562 ◽

Cited By ~ 34

Author(s):

Vanessa Yardley ◽

Diane Snowdon ◽

Simon Croft ◽

Banasri Hazra

Keyword(s):

Trypanosoma Cruzi ◽

Trypanosoma Brucei ◽

Leishmania Donovani ◽

Vitro Activity ◽

In Vitro Activity ◽

Trypanosoma Brucei Brucei

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Comparison of the cytolytic effects in vitro on Trypanosoma brucei brucei of plasma, high density lipoproteins, and apolipoprotein A-I from hosts both susceptible (cattle and sheep) and resistant (human and baboon) to infection.

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)41617-7 ◽

1992 ◽

Vol 33 (4) ◽

pp. 513-523

Author(s):

MP Gillett ◽

JS Owen

Keyword(s):

Trypanosoma Brucei ◽

High Density ◽

High Density Lipoproteins ◽

Trypanosoma Brucei Brucei ◽

Apolipoprotein A ◽

Plasma High Density ◽

Cattle And Sheep

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

Biochemical Journal ◽

10.1042/bj20051886 ◽

2006 ◽

Vol 396 (2) ◽

pp. 277-285 ◽

Cited By ~ 46

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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Cross-Resistance to Nitro Drugs and Implications for Treatment of Human African Trypanosomiasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00332-10 ◽

2010 ◽

Vol 54 (7) ◽

pp. 2893-2900 ◽

Cited By ~ 69

Author(s):

Antoaneta Y. Sokolova ◽

Susan Wyllie ◽

Stephen Patterson ◽

Sandra L. Oza ◽

Kevin D. Read ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Human African Trypanosomiasis ◽

Parent Drug ◽

Cross Resistance ◽

Pharmacokinetic Studies ◽

African Trypanosomiasis ◽

Trypanosoma Brucei Brucei ◽

Resistant Lines

ABSTRACT The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection in vitro by exposure to increasing concentrations of nifurtimox, Trypanosoma brucei brucei nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (∼27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole in vivo. In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy.

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