scholarly journals Benzimidazole inhibitors of the major cysteine protease of Trypanosoma brucei

2019 ◽  
Vol 11 (13) ◽  
pp. 1537-1551 ◽  
Author(s):  
Glaécia AN Pereira ◽  
Lucianna H Santos ◽  
Steven C Wang ◽  
Luan C Martins ◽  
Filipe S Villela ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Cysteine Proteases ◽  
African Trypanosomiasis ◽  
High Similarity ◽  
Trypanosoma Brucei Brucei ◽  
Structure Activity ◽  
Starting Point ◽  
Competitive Inhibitors ◽  
Enzyme Selectivity

Aim: Limitations in available therapies for trypanosomiases indicate the need for improved medicines. Cysteine proteases cruzain and rhodesain are validated targets for treatment of Chagas disease and human African trypanosomiasis. Previous studies reported a benzimidazole series as potent cruzain inhibitors. Results & methodology: Considering the high similarity between these proteases, we evaluated 40 benzimidazoles against rhodesain. We describe their structure-activity relationships (SAR), revealing trends similar to those observed for cruzain and features that lead to enzyme selectivity. This series comprises noncovalent competitive inhibitors (best Ki = 0.21 μM against rhodesain) and micromolar activity against Trypanosoma brucei brucei. A cheminformatics analysis confirms scaffold novelty, and the inhibitors described have favorable predicted physicochemical properties. Conclusion: Our results support this series as a starting point for new human African trypanosomiasis medicines.

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

2010 ◽  
Vol 54 (7) ◽  
pp. 2893-2900 ◽  
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.

IgM, lgG and IL-6 profiles in the Trypanosoma brucei brucei monkey model of human African trypanosomiasis

Acta Tropica ◽  
2017 ◽  
Vol 168 ◽  
pp. 45-49 ◽  
Author(s):  
Maxwell W. Waema ◽  
Naomi W. Maina ◽  
Maina Ngotho ◽  
Simon M. Karanja ◽  
Beatrice M. Gachie ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
African Trypanosomiasis ◽  
Trypanosoma Brucei Brucei ◽  
Monkey Model

The Inhibition of Cysteine Proteases Rhodesain and TbCatB: A Valuable Approach to Treat Human African Trypanosomiasis

2016 ◽  
Vol 16 (17) ◽  
pp. 1374-1391 ◽  
Author(s):  
Roberta Ettari ◽  
Santo Previti ◽  
Lucia Tamborini ◽  
Gregorio Cullia ◽  
Silvana Grasso ◽  
...  
Keyword(s):  
Human African Trypanosomiasis ◽  
Cysteine Proteases ◽  
African Trypanosomiasis

New Pd-Fe ferrocenyl antiparasitic compounds with bioactive 8-hydroxyquinoline ligands: a comparative study with their Pt-Fe analogues

2021 ◽  
Author(s):  
Feriannys Rivas ◽  
Andrea Medeiros ◽  
Cristina Quiroga ◽  
Diego Benítez ◽  
Marcelo Comini ◽  
...  
Keyword(s):  
Comparative Study ◽  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
African Trypanosomiasis

In the search for a more effective chemotherapy for the treatment of Human African Trypanosomiasis, the disease caused by the parasite Trypanosoma brucei, the development of ferrocenyl compounds has arisen...

Human African trypanosomiasis

2010 ◽  
pp. 1119-1127
Author(s):  
August Stich
Keyword(s):  
West Africa ◽  
East Africa ◽  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Protozoan Parasite ◽  
Sleeping Sickness ◽  
Tsetse Flies ◽  
African Trypanosomiasis ◽  
Tropical Africa

Human African trypanosomiasis (HAT, sleeping sickness) is caused by two subspecies of the protozoan parasite Trypanosoma brucei: T. b. rhodesiense is prevalent in East Africa among many wild and domestic mammals; T. b. gambiense causes an anthroponosis in Central and West Africa. The disease is restricted to tropical Africa where it is transmitted by the bite of infected tsetse flies (...

Human African trypanosomiasis

2020 ◽  
pp. 1451-1459
Author(s):  
Reto Brun ◽  
Johannes Blum
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Specific Treatment ◽  
Protozoan Parasite ◽  
Control Measures ◽  
Tsetse Flies ◽  
African Trypanosomiasis ◽  
Control Programmes ◽  
The 1960S ◽  
Stage 1

Human African trypanosomiasis (sleeping sickness) is caused by subspecies of the protozoan parasite Trypanosoma brucei. The disease is restricted to tropical Africa where it is transmitted by the bite of infected tsetse flies (Glossina spp.). Control programmes in the 1960s were very effective, but subsequent relaxation of control measures led to recurrence of epidemic proportions in the 1980s and 1990s. Control is now being regained. Untreated human African trypanosomiasis is almost invariably fatal. Specific treatment depends on the trypanosome subspecies and the stage of the disease. Drugs used for stage 1 include pentamidine and suramin, and for stage 2 include melarsoprol, eflornithine, and nifurtimox, but regimens are not standardized, and treatment is difficult and dangerous; all of the drugs used have many side effects, some potentially lethal.

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