Praziquantel structure

Figure 5.54 Structures of Praziquantel and its metabolites, cis- and fraw5-4-hydroxy-praziquantel. Reprinted from 7. Chromatogr., B, 708, Lerch, C. and Blaschke, G., Investigation of the stereoselective metabolism of Praziquantel after incubation with rat liver microsomes by capillary electrophoresis and liquid chromatography-mass spectrometry , 267-275, Copyright (1998), with permission from Elsevier Science.

Piperazine fused polycyclic ring systems are unique in terms of structures and properties. Praziquantel 211 is the primary medication for human schistosomiasis, for which it is usually effective in a single dose treatment. As shown in Fig. 10, praziquantel consists of a ketopiperazine fused ring system. A co-crystal of praziquantel and glutathione-5-peroxidase of the helminth Schistosoma japonica was known [63]. Praziquantel binds in a channel joining the two xenobiotic substrate... 

Fig. 10 X-ray co-crystal structure of praziquantel 211 and glutathione-S-peroxidase complex (PDB ID IGTB). Praziquantel is shown as yellow sticks and the receptor binding site is shown as hydrophobic surface...

Fig. 4.9 Chemical structures of diamphenethide, praziquantel, clorsulon, and hygromycin B.

The discovery of the anthelmintic activity of the pyrazinoisoquinolines [25,31,32] initiated the synthesis of a variety of substituted pyrazinoisoquinolines. Praziquantel was picked up from more than 400 l,2,3,6,7,llb-hexahydro-4H-pyraz-ino[2,l-a]isoquinolin-4-ones and related compounds, because of its potent and broad spectrum biological activity [26]. The structure activity relationship in the analogues of praziquantel would indicate that positions 2 and 4 are the most critical positions, which govern the cestodicidal as well as antischistosomal activities in the pyrazinoisoquinolines. 

Some praziquantel derivatives with substitutions in the benzene ring and other positions of the ring system have also been synthesised. Such structural variations had minor influence on the biological activity. Consequently a number of active analogues were found, but none exceeded the potency of praziquantel [26,33]. 

Praziquantel (PQ) (Table 7-10), a pyrazinoisoquinoline, can be viewed as having evolved from mirasan by optimizing structural features of compound V (Fig. 7-14). For all intents and purposes it is the first really broad-spectrum anthelmintic that is effective against all schistosomes and most other flukes, such as liver, intestinal, and lung (see Table 7-9 for species). PQ is rapidly becoming the drug of choice for many of the preceding infections, as well as for the cestodes (tapeworms). 

H. S. Rosenkranz, Y. P. Zhang and G. Klopman, Risk identification using structural concepts the potential carcinogenicity of praziquantel, Regul. Toxicol. Pharmacol., 1995, 22, 152 161. 

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