Structure–Activity Relationship and in Vitro Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Studies of N-aryl 3-Trifluoromethyl Pyrido[1,2-a]benzimidazoles That Are Efficacious in a Mouse Model of Schistosomiasis

Mayoka, Godfrey; Keiser, Jennifer; Häberli, Cécile; Chibale, Kelly

doi:10.1021/acsinfecdis.8b00313

Cited by 13 publications

(7 citation statements)

References 17 publications

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“…Intrinsic dissolution rate profiles in water at 37 • C for PZQ-HH, Form B and Form A.The hemihydrate form was assayed for its activity in vitro against S. mansoni adults: it exhibited an IC 50 of 0.15 µM, identical to commercially available Form A (IC 50 of 0.1. µM)[48].…”

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confidence: 99%

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties

et al. 2020

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Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and deposited in the Cambridge Structural Database (CSD). This work adds to the list of multicomponent forms of PZQ a relevant example of a racemic hemihydrate (PZQ-HH), obtainable from commercial PZQ (polymorphic Form A) through mechanochemistry. Noteworthy, the formation of the new hemihydrate strongly depends on the initial polymorphic form of PZQ and on the experimental conditions used. The new PZQ-HH has been fully characterized by means of HPLC, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Hot-Stage Microscopy (SEM), Powder X-Ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), FT-IR, polarimetry, solid-state NMR (SS-NMR), solubility and intrinsic dissolution rate (IDR), and in vitro tests on Schistosoma mansoni adults. The crystal structure was solved from the powder X-ray diffraction pattern and validated by periodic-DFT calculations. The new bioactive hemihydrate was physically stable for three months and showed peculiar biopharmaceutical features including enhanced solubility and a double intrinsic dissolution rate in water in comparison to the commercially available PZQ Form A.

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confidence: 99%

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties

et al. 2020

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“…In this study, most pyrazolines tested had SI value ≥ 10, demonstrating the highly selective anthelmintic effect of pyrazolines. Comparatively, the SI values achieved with pyrazolines exceeded those obtained for other relevant heterocyclic compounds with antischistosomal properties 21 , 22 . Although the SI values recorded for pyrazolines were more than 10 times below those for the reference drug praziquantel, a SI value ≥ 10 fulfills and exceeds the criteria established by the WHO for potential compounds as anthelmintic agents 20 .…”

Section: Resultsmentioning

confidence: 62%

“…The pyrazolines were synthesized according to a previously published procedure 22 . A solution of the appropriate chalcone (1 eq.)…”

Section: Methodsmentioning

confidence: 99%

Pyrazoline derivatives as promising novel antischistosomal agents

Morais

Mengarda

Miguel

et al. 2021

Sci Rep

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Praziquantel is the only available drug to treat schistosomiasis, a parasitic disease that currently infects more than 240 million people globally. Due to increasing concerns about resistance and inadequate efficacy there is a need for new therapeutics. In this study, a series of 17 pyrazolines (15–31) and three pyrazoles (32–34) were synthesized and evaluated for their antiparasitic properties against ex vivo adult Schistosoma mansoni worms. Of the 20 compounds tested, six had a 50% effective concentration (EC50) below 30 μM. Our best hit, pyrazoline 22, showed promising activity against adult schistosomes, with an EC50 < 10 µM. Additionally, compound 22 had low cytotoxicity, with selectivity index of 21.6 and 32.2 for monkey and human cell lines, respectively. All active pyrazolines demonstrated a negative effect on schistosome fecundity, with a marked reduction in the number of eggs. Structure–activity relationship analysis showed that the presence of the non-aromatic heterocycle and N-substitution are fundamental to the antischistosomal properties. Pharmacokinetics, drug-likeness and medicinal chemistry friendliness studies were performed, and predicted values demonstrated an excellent drug-likeness profile for pyrazolines as well as an adherence to major pharmaceutical companies’ filters. Collectively, this study demonstrates that pyrazoline derivatives are promising scaffolds in the discovery of novel antischistosomal agents.

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“…A linear correlation between in vitro activity and β‐hematin inhibition was absent, suggesting that this is only a contributing part of the MOA . Further optimisation resulted in compounds such as 82 , which displayed improved in vitro activity against both newly transformed schistosoma as well as adult worms, which translated into promising in vivo activity, rendering this class of compounds as promising leads for future anti‐schistosoma drug discovery …”

Section: Anti‐schistosomal Agentsmentioning

confidence: 99%

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

Veale

Müller

2020

ChemMedChem

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Global advancements in biological technologies have vastly increased the variety of and accessibility to bioassay platforms, while simultaneously improving our understanding of druggable chemical space. In the South African context, this has resulted in a rapid expansion in the number of medicinal chemistry programmes currently operating, particularly on university campuses. Furthermore, the modern medicinal chemist has the advantage of being able to incorporate data from numerous related disciplines into the medicinal chemistry process, allowing for informed molecular design to play a far greater role than previously possible. Accordingly, this review focusses on recent highlights in drug-discovery programmes, in which South African medicinal chemistry groups have played a substantive role in the design and optimisation of biologically active compounds which contribute to the search for promising agents for infectious disease.

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Structure–Activity Relationship and in Vitro Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Studies of N-aryl 3-Trifluoromethyl Pyrido[1,2-a]benzimidazoles That Are Efficacious in a Mouse Model of Schistosomiasis

Cited by 13 publications

References 17 publications

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties

Pyrazoline derivatives as promising novel antischistosomal agents

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

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