Kinetoplastid Parasites

Geldern, Tomas von; Harhay, Michael O.; Scandale, Ivan; Don, Robert

doi:10.1007/7355_2011_17

Cited by 6 publications

(4 citation statements)

References 220 publications

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“…Interestingly, besides being a good inhibitor of T. b. brucei proliferation, 20b was also an excellent inhibitor of T. b. rhodesiense (IC 50 = 60 nM, Table ), the causative agent of acute East-African HAT, for which the only treatment is the arsenic-containing drug melarsoprol, associated with fatal encephalopathy in 5–10% patients . Moreover, 20b also showed some activity against T. cruzi , the causative agent of Chagas disease .…”

Section: Resultsmentioning

confidence: 99%

Catechol Pyrazolinones as Trypanocidals: Fragment-Based Design, Synthesis, and Pharmacological Evaluation of Nanomolar Inhibitors of Trypanosomal Phosphodiesterase B1

Orrling¹,

Jansen

et al. 2012

J. Med. Chem.

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Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC₅₀ values down to 49 nM. The compounds also block parasite proliferation (e.g., VUF13525 (20b): T. brucei rhodesiense IC₅₀ = 60 nM, T. brucei brucei IC₅₀ = 520 nM, T. cruzi = 7.6 μM), inducing a typical multiple nuclei and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target.

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Section: Resultsmentioning

confidence: 99%

Catechol Pyrazolinones as Trypanocidals: Fragment-Based Design, Synthesis, and Pharmacological Evaluation of Nanomolar Inhibitors of Trypanosomal Phosphodiesterase B1

Orrling¹,

Jansen

et al. 2012

J. Med. Chem.

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“…Chagas disease is currently endemic in 21 countries across Latin America, killing more people in the region each year than any other parasite-born disease including malaria. Moreover, its prevalence is growing in nonendemic developed countries, including Australia, USA, Japan, and Spain, such that the global health burden is around 10 million cases and 25 million people at risk. − Recent efforts from Product Development Partnerships (PDPs) such as the Drugs for Neglected Diseases initiative (DND i ) have brought this parasitic disease to the forefront of research efforts into neglected diseases, expanding on decades of work undertaken in Central and South America and in dedicated laboratories worldwide. , …”

Section: Introductionmentioning

confidence: 99%

Analogues of Fenarimol Are Potent Inhibitors of Trypanosoma cruzi and Are Efficacious in a Murine Model of Chagas Disease

et al. 2012

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We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi ( T. cruzi ), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC(50)s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.

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“…Amongst them are parasites of the Trypanosoma brucei species complex, which cause human African trypanosomiasis (HAT), also known as sleeping sickness. In the early stage of the disease, parasites invade the blood and lymphatic system, while in the second stage, they penetrate the blood-brain-barrier (BBB) and enter the central nervous system (CNS), leading to coma and death if untreated [2]. The current drugs used to treat HAT, pentamidine, suramin, melarsoprol and nifurtimox-eflornithine combination therapy (NECT) [1], are toxic and not always effective.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2-arylbenzimidazoles

Bistrović

Krstulović

Koštrun

et al. 2020

European Journal of Medicinal Chemistry

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Kinetoplastid Parasites

Cited by 6 publications

References 220 publications

Catechol Pyrazolinones as Trypanocidals: Fragment-Based Design, Synthesis, and Pharmacological Evaluation of Nanomolar Inhibitors of Trypanosomal Phosphodiesterase B1

Catechol Pyrazolinones as Trypanocidals: Fragment-Based Design, Synthesis, and Pharmacological Evaluation of Nanomolar Inhibitors of Trypanosomal Phosphodiesterase B1

Analogues of Fenarimol Are Potent Inhibitors of Trypanosoma cruzi and Are Efficacious in a Murine Model of Chagas Disease

Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2-arylbenzimidazoles

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