Development of chiral praziquantel analogues as potential drug candidates with activity to juvenile Schistosoma japonicum

Zheng, Yang; Dong, Lanlan; Hu, Changyan; Zhao, Bo; Yang, Chunhua; Xia, Chao-Ming; Sun, Dequn

doi:10.1016/j.bmcl.2014.07.039

Cited by 20 publications

(20 citation statements)

References 18 publications

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“…Overall, all chiral PZQ derivatives display modest activity in vivo compared to that of PZQ1. Intriguingly, the size of the ring with a carbonyl group in these derivatives had an appreciable impact on R isomers, increasing their activity, but had almost no effect on S isomers (55). Using organometallic moieties such as ferrocenyl (already present in anticancer, antibacterial, and antimalarial drugs [56][57][58]) Fc-PZQ derivatives (types A and B, Fig.…”

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

279

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

279

244

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“…( R )-PZQ and ( S )-PZQ were obtained with an improved method based on the reported procedure, 17 with the enantiomeric excess value >99% by high-performance liquid chromatography.…”

Section: Methodsmentioning

confidence: 99%

The cytotoxicity study of praziquantel enantiomers

Sun¹,

Mao²,

Wang³

et al. 2016

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Praziquantel (PZQ) is prescribed as a racemic mixture (racemic-PZQ, rac-PZQ), which is composed of (R)-PZQ and (S)-PZQ. In this work, the cytotoxicity of rac-PZQ and its two enantiomers (R)-PZQ and (S)-PZQ on eight cell lines (L-02, HepG2, prf-plc-5, SH-SY5Y, HUVEC, A549, HCT-15, Raw264.7) was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-nyltetrazolium bromide and lactate dehydrogenase assays. The morphology of apoptotic cells was studied by fluorescence microscope using Hoechst 33342 staining, and the cytotoxicity of the compounds was also tested by lactate dehydrogenase assay. Results revealed that (R)-PZQ had negligible cytotoxicity against L-02, SH-SY5Y, HUVEC, A549, HCT-15, and Raw264.7 cells but selectively inhibited tumor cell lines (prf-plc-5 and HepG2). However, in contrast to (R)-PZQ, the (S)-isomer showed higher cytotoxicity against L-02 cells and lower inhibition on prf-plc-5 and HepG2 cells. Besides, (R)-PZQ showed lower cytotoxicity on SH-SY5Y cells than (S)-PZQ. Meanwhile, (R)-PZQ at <80 μM concentration could promote proliferation of macrophage cells (Raw264.7). Our research revealed that (R)-PZQ has lower cytotoxicity than (S)-PZQ and has similar cytotoxicity with rac-PZQ. (S)-PZQ is the principal enantiomer to cause side effects on human definitive hosts. These findings gave the reasonable reasons for World Health Organization to produce (R)-PZQ as a replacement for rac-PZQ for the treatment of schistosomiasis.

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“…Furthermore, the presence of zone 4 evidences the recycling of the desorbent, which means less fresh desorbent should be consumed, is what increases the efficiency of the process. This is an interesting scenario, which allows further studies involving racemization and synthesis of PZQ analogs to fight against resistant and immature parasites . The actual SMB unit used in the present paper is going to help the development of control strategies, like NMPC, to provide in a semipreparative scale enantiomers with different optical purities, maximum productivity, and minimum desorbent consumption.…”

Section: Introductionmentioning

confidence: 99%

“…Trying to overcome this issue, researches are still in progress to generate a pioneering medicine to fight against many parasitic diseases mainly using racemates (eg, capsules) [4][5][6][7] or L-and D-PZQ in different proportions (eg, orally dispersible tablets with one fourth the size of commercial ones). 8 Better understanding of mechanism of action of pure PZQ enantiomers against Schistosoma bodies, [9][10][11][12][13] new molecular formulas to fight against adult 10,11,[14][15][16] and juvenile 13,17,18 worms should be also important issues to be studied using pure L-PZQ. Nowadays, racemate (rac-PZQ) is used in most of these studies.…”

Section: Introductionmentioning

confidence: 99%

Separation of praziquantel enantiomers using simulated moving bed chromatographic unit with performance designed for semipreparative applications

et al. 2019

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Praziquantel (PZQ) composes a regular medicine available in a tablet form to fight schistosomiasis and just half of its mass is composed by the active principle (L‐PZQ), the other half, D‐PZQ, is frequently associated to a strong bitter taste. Moreover, optically pure L‐PZQ derivatives could be used in studies about adult and juvenile worms' resistance. Nowadays, these studies use racemic PZQ (rac‐PZQ) as starting point. The D‐PZQ, which would be discarded, could be racemized, coming back as feed concentration in the process. The present work aims to get L‐PZQ and D‐PZQ with high optical purities (more than 97%) and productivity (more than 253 g kgads−1 day−1) towards semipreparative scale for researches involving L‐PZQ, L‐PZQ derivatives, and D‐PZQ racemization. In order to achieve this goal, a built‐in‐house simulated moving bed chromatographic unit with the cellulose tris (3‐chloro‐4‐methylphenylcarbamate) (Chiralcel OZ) as chiral stationary phase (CSP) was used to investigate different scenarios of separation according to a well‐known design method called triangle theory. In all scenarios investigated, at least one of the outlet streams presented high optically purity for one of the enantiomers. Comparison with literature showed superior performance of our unit even at racemic mixture concentrations that were 10 times lower than the racemic concentrations found in literature.

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Development of chiral praziquantel analogues as potential drug candidates with activity to juvenile Schistosoma japonicum

Cited by 20 publications

References 18 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

The cytotoxicity study of praziquantel enantiomers

Separation of praziquantel enantiomers using simulated moving bed chromatographic unit with performance designed for semipreparative applications

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