Abstract:
Chapter one of this thesis presents a review about aliphatic nucleophilic substitution and the mechanisms attributed to aliphatic nucleophilic substitution like the SN1, SN2, SNi, neighbouring group.
There is also a review about the pro-drug and its purposes, pro-drug of functional groups and bioprecursor pro-drug.
The disconnection approach and retrosynthetic analysis, with some examples of related disconnection were reviewed and discussed.
Also in this chapter there is a review about praziquantel, including, its biotransformation, bioavailability, synthesis, analysis and drug resistance.
In the present work eighteen novel compounds were designed as possible anthelmintics, synthesized and characterized. These compounds shared (and lack) certain features of praziquantel.
Designing of the prepared compounds together with the appropriate retrosynthetic analysis of the target molecules were given.
Possible mechanistic explanations beside the mechanisms of representative reactions were discussed and illustrated.
In this work the praziquantel is treated by sodium hydroxide (alkaline hydrolysis) to obtain the open lactam form of the PZQ which is then treated by several reagents to give the required compounds, which are divided into three main groups. In the first group the open lactam form is treated by benzyl chloride to give the N-benyzl / benzyl ester derivative, the latter was hydrolyzed to obtain the N- benzyl derivatives. with the second group the open lactam form is treated by benzoyl chloride to give the carboxamide derivative; the latter was esterified by (MeOH, EtOH, benzyl alcohol) to give the ester derivatives for the carboxamide. The last group is the sulphonamide group which is further divided into three groups. one of these was obtained by treating the open lactam form by benzene sulphonyl chloride and then esterifing by (MeOh, EtOH, n. PrOH). the second was obtained by treating the open lactam by p.toluene sulphonyl chloride and then esterifing by the same alcohols.The last group was obtained by treating the open lactam form by p.bromobenzene sulphonyl chloride followed by esterification by the same alcohols.
The praziquantel is subjected to different types of hydrolysis by different acids, bases and conditions to obtain the open lactam form. the alkaline hydrolysis by NaOH is the best of all others in its purity and percentage yield and identity of the product.
All the synthesized compounds were subjected to different kinds of analysis as melting point, TLC, UV, I.R., NMR and MS. the compounds showed characteristic spectral bands in the I.R, similar absorptions in the uV, similar NMR signals and similar fragment pattern in the M.S. compounds I, II, III, IV, V were tested for the biocyclization but no one of them was converted to PZQ or one of its metabolites. hplc was adopted as a suitable method for detection of the different metabolites in the sera of chicks used in this study.
