Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi

Varghese, Swapna; Rahmani, Raphaël; Russell, Stephanie; Deora, Girdhar Singh; Ferrins, Lori; Toynton, Arthur; Jones, Amy J.; Sykes, Melissa; Kessler, Albane; Eufrásio, Amanda; Cordeiro, Artur T.; Sherman, Julian; Rodrı́guez, Ana; Avery, Vicky M.; Piggott, Matthew; Baell, Jonathan B.

doi:10.1021/acsmedchemlett.9b00218

Cited by 17 publications

(11 citation statements)

References 16 publications

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“…Treatment options for Chagas disease remain limited. Efforts to expand the scope of chemical scaffolds for drug discovery programs against T. cruzi using natural product, de novo design, and drug repositioning approaches have yielded promising new leads in recent years 9,16,[22][23][24][25] . Here, we used a high-throughput screening and bioactivity-guided fractionation pipeline to identify five potent leucinostatins from an Ophiocordyceps sp.…”

Section: Discussionmentioning

confidence: 99%

Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi

Bernatchez

Y²,

et al. 2021

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Safe and effective treatments for Chagas disease, a potentially fatal parasitic infection associated with cardiac and gastrointestinal pathology and caused by the kinetoplastid parasite Trypanosoma cruzi, have yet to be developed. Benznidazole and nifurtimox, which are currently the only available drugs against T. cruzi, are associated with severe adverse effects and questionable efficacy in the late stage of the disease. Natural products have proven to be a rich source of new chemotypes for other infectious agents. We utilized a microscopy-based high-throughput phenotypic screen to identify inhibitors of T. cruzi from a library of natural product samples obtained from fungi procured through a Citizen Science Soil Collection Program (https://whatsinyourbackyard.org/), and the Great Lakes (USA) benthic environment. We identified five leucinostatins (A, B, F, NPDG C and NPDG D) as potent inhibitors of the intracellular amastigote form of T. cruzi. Leucinostatin B also showed in vivo efficacy in a mouse model of Chagas disease. Given prior reports that leucinostatins A and B have antiparasitic activity against the related kinetoplastid T. brucei, our findings suggest a potential cross-trypanocidal compound class and provide a platform for further chemical derivatization of a potent chemical scaffold against T. cruzi.

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Section: Discussionmentioning

confidence: 99%

Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi

Bernatchez

Y²,

et al. 2021

Preprint

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“…brucei or T . cruzi+/- fibroblasts from in-vitro cultures as described previously [ 20 ]) were added at a concentration of 1:10 (B-cell: infected cell), as measured before lysis. Parasite and cell lysates were prepared in B-cell medium by 10 freeze/thaw cycles.…”

Section: Methodsmentioning

confidence: 99%

“…TLR7 agonist R848 (Mabtech) was used at 1 μg/ml; anti-BCR (Fab 0 ) 2 anti-IgM (The Jackson Laboratory) was used at 5 μg/ml, and IFN-γ (Peprotech) at 100 U/ml. Uninfected (3T3 mouse fibroblasts) and infected parasite lysates (P. yoelii 17XNL strain from mice-infected blood [12], T. b. brucei or T. cruzi+/-fibroblasts from in-vitro cultures as described previously [20]) were added at a concentration of 1:10 (B-cell: infected cell), as measured before lysis. Parasite and cell lysates were prepared in B-cell medium by 10 freeze/thaw cycles.…”

Section: In Vitro Activation Assaysmentioning

confidence: 99%

Autoimmunity to phosphatidylserine and anemia in African Trypanosome infections

et al. 2021

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Anemia caused by trypanosome infection is poorly understood. Autoimmunity during Trypanosoma brucei infection was proposed to have a role during anemia, but the mechanisms involved during this pathology have not been elucidated. In mouse models and human patients infected with malaria parasites, atypical B-cells promote anemia through the secretion of autoimmune anti-phosphatidylserine (anti-PS) antibodies that bind to uninfected erythrocytes and facilitate their clearance. Using mouse models of two trypanosome infections, Trypanosoma brucei and Trypanosoma cruzi, we assessed levels of autoantibodies and anemia. Our results indicate that acute T. brucei infection, but not T. cruzi, leads to early increased levels of plasma autoantibodies against different auto antigens tested (PS, DNA and erythrocyte lysate) and expansion of atypical B cells (ABCs) that secrete these autoantibodies. In vitro studies confirmed that a lysate of T. brucei, but not T. cruzi, could directly promote the expansion of these ABCs. PS exposure on erythrocyte plasma membrane seems to be an important contributor to anemia by delaying erythrocyte recovery since treatment with an agent that prevents binding to it (Annexin V) ameliorated anemia in T. brucei-infected mice. Analysis of the plasma of patients with human African trypanosomiasis (HAT) revealed high levels of anti-PS antibodies that correlated with anemia. Altogether these results suggest a relation between autoimmunity against PS and anemia in both mice and patients infected with T. brucei.

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“…Pyrazole N-ethylurea derivatives showed potent activity against T. brucei brucei and T. cruzi, with a drastic reduction of parasitemia after 6 days of treatment and efficacy in the murine model of acute T. cruzi infection. The SAR study for N-ethylurea pyrazole derivatives revealed that the meta position in the aromatic ring substantially influences the trypanocidal activity, with the compounds with fluorine and chlorine substituents being the most effective [37].…”

Section: Structure-activity Relationship (Sar) Of Pyrazole Derivativesmentioning

confidence: 99%

Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi

et al. 2021

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Chagas disease, a chronic and silent disease caused by Trypanosoma cruzi, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a T. cruzi cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds 3g, 3j, and 3m as promising candidates, with IC50 values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure–activity relationship (SAR) analysis revealed increased potency of 1-aryl-1H-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the para-position. The 3m compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies.

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Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi

Cited by 17 publications

References 16 publications

Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi

Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi

Autoimmunity to phosphatidylserine and anemia in African Trypanosome infections

Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi

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