Praziquantel analogs with activity against juvenile Schistosoma mansoni

Dong, Yuxiang; Chollet, Jacques; Vargas, Mireille; Mansour, Nuha R.; Bickle, Q. D.; Alnouti, Yazen; Huang, Jiangeng; Keiser, Jennifer; Vennerstrom, Jonathan L.

doi:10.1016/j.bmcl.2010.03.001

Cited by 59 publications

(53 citation statements)

References 21 publications

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“…4) led to a moderate reduction of worm motility in vitro, but generally, this activity was not observed in vivo. However, one derivative of these series, PZQ7, stood out in regard to significant activity in vivo, which may derive from its in vivo reduction to a transcyclohexanol metabolite, PZQ4 (54). With this structure in mind, chiral PZQ derivatives (PZQ10 and PZQ11) were developed, as well as chiral PZQ7.…”

Section: And S-trans-and S-cis-4-oh-pzq While Pzq2 Is Metabolized Tomentioning

confidence: 99%

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Vale

Gouveia

Rinaldi

et al. 2017

Antimicrob Agents Chemother

278

244

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Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drugresistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.

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Section: And S-trans-and S-cis-4-oh-pzq While Pzq2 Is Metabolized Tomentioning

confidence: 99%

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Vale

Gouveia

Rinaldi

et al. 2017

Antimicrob Agents Chemother

278

244

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“…15,16,24,31,32 The optically pure four (η 6 -PZQ)Cr(CO) 3 derivatives were prepared using R-PZQ and S-PZQ following a procedure reported for synthesis of 1 and 2. 15 The purities of compounds ( 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 with an electrospray ionization source.…”

Section: Praziquanamine Trans-4-pzq-oh and Cis-4-pzq-oh R-pzq And Smentioning

confidence: 99%

In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η⁶-Praziquantel)Cr(CO)₃ Derivatives

Ingram

Leonidova²,

Pierroz³

et al. 2013

J. Med. Chem.

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ABSTRACT. The in vitro metabolic behavior was investigated of two chromium tricarbonyl derivatives of the antischistosomal drug Praziquantel (PZQ) with the formula (η 6 -PZQ)Cr(CO) 3(1 and 2), using human liver microsomes. It could be demonstrated that the metabolic profiles of the derivatives differ significantly. The optically pure (η 6 -PZQ)Cr(CO) 3 derivatives, (S, Sp)-1,were also prepared to assess of the eudysmic ratios of 1 and 2 against S. mansoni. A strong enantioselective antischistosomal activity was observed. The Renantiomers are highly active against adult schistosomes in vitro (IC 50 : 0.08 -0.13 µM) whereas both S-enantiomers lack activity. The in vivo activity of 1 and 2 was then studied in mice harboring a chronic Schistosoma mansoni (S. mansoni) infection. A single dose of 1 and 2 (400 mg/kg) resulted in low worm burden reductions of 24 and 29 % (p>0.05).

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“…Of high interest, Vennerstrom and co-workers recently prepared PZQ derivatives with activity against the juvenile stage of S. mansoni. 12 Nonetheless, to the best of our knowledge, no lead compound suitable for further preclinical testing was identified in these studies. This fact clearly emphasizes the need for a fundamentally different approach for the discovery of novel PZQ derivatives active against schistosomiasis.…”

Section: Introductionmentioning

confidence: 97%

Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

et al. 2012

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The design, synthesis and biological evaluation of eighteen ferrocenyl derivatives (4A-12A and 4B-12B) of the most-well known drug against schistosomiasis, namely praziquantel (PZQ), are reported.These compounds which have been all isolated as racemates were unambiguously characterized by 1 H and 13 C NMR spectroscopy, mass spectrometry and elemental analysis as well as by X-ray crystallography for 4A, 5A and 7A. Cytotoxicity studies revealed that the complexes were moderately toxic towards a cervical cancer cell line (HeLa) and, importantly, significantly less active towards a noncancerous cell line (MRC-5). The in vitro anthelmintic activity of the eighteen ferrocenyl PZQ derivatives was tested against Schistosoma mansoni and values in the micromolar range (26-68 µM) were determined for the four most active compounds. It was also demonstrated using two compounds of the series as models (8A and 8B) that the complexes were stable when incubated for 24 h at 37°C in human plasma. 3Introduction.

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Praziquantel analogs with activity against juvenile Schistosoma mansoni

Cited by 59 publications

References 21 publications

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η⁶-Praziquantel)Cr(CO)₃ Derivatives

Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

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Praziquantel analogs with activity against juvenile Schistosoma mansoni

Cited by 59 publications

References 21 publications

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η6-Praziquantel)Cr(CO)3 Derivatives

Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

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In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η⁶-Praziquantel)Cr(CO)₃ Derivatives