The preparation and investigation of the anthelmintic and antimicrobial activities of some d erivatives of the open -lactam form of praziq uantel .


Research type: Research Paper

Authors: Saeed, Ahmed Elsadig Mohammed .

Abstract: The lactam ring of the parent praziquantel was opened through hot alkaline hydrolysis. The resultant open lactam form of praziquantel (OLF-PZQ) has been subjected to various functionalization and iterconversions of the amino and carboxylic acid (-NH/COOH) group. Sixteen compounds have been designed, synthesized and their chemical structures were spectroscopically elucidated (using I.R., up1H-and up13C--NMR, MS and GC-MS). These derivatives cover a range of -N-alkyl, -N-carboxamide, -N-sulphonamide and their estern NH/-COOalkyl were prepared, but they have been found to cyclize rapidly at room temperature to the parent praziquantel. A similar behavior of cyclization was shown by the -NH-COOH (OLF-PZQ) in alcohol-acid media. The methods of synthesis, and the mechanism for some selected ractions are given and discussed. The in VITRO CYCLIZATION of the (OLF-PZQ) and its derivatives to praziquantel is considered in this study. Representatives of the diffferent classes of compounds were selected and tested for their antischistosomal activity against S. MANSONI in albino mice. These compounds were:- NCHsup2CHsup3/COOH (V11), -N-CO-CHsup3/-COOH (1) and -N-sulphonamide/-COOH (X11) (fingur 2.1), together with (OLF-PZQ) and praziquantel. The compounds were given orally to the infected animals in a dose of 40 mg/kg body weight. Different indicator parameters were used to assess the activity. The percentage of worms reduction in the treated groups (praziquantel 16.6 percent, N-(1,2,3,4-tetrahydro-1-isoquinoly1 methy1)-N-cyclohexyl carbony1 glcine (OLF-PZQ) = 28.6 percent, N-(1,2,3,4tetrahydro-2-acety1-1-isoquinoly1 meth1)-N-cyclohezyl carbonyl glycine (1) = 42.8 percent, N-(1,2,3,3-tetrahydro-2-ethy1-1-isoquinnoly1 methy1)-N-cyclohexy1 carbony1 glycine (Viii) = 100 percent and N-(1,2,3,4-tetrahydro-2-(4-aminobenzene sulphonyl1)-1-isoquinolylmethy1)-N-cyclohexy1 carbony1 glycine (X11) = 88 percent compared to the infected control group). These results indicated that these compounds were more effective on worms reduction that praziquantel. It can be seen that, compound (V111) has six folds the antischistosomal activity of praziquanttel. All the observed toxicolofical findings were mainly due to the effect of the eggs rather than the compounds themselves. All the compounds have been found to possess anticestodal activity when tested against R-TETRAGONA IN BOVANS type chicks, tanged from 14 to 100 percent, in a dose of 20 mg/kg body weight given twice in 72 hours. Higher efficacy (100 percent) was recorded at the first dose in the (-NR/-COOH and -NR/-COOR, R=alky1)series of compounds in a similar fashion to praziquantel (100 percent). Lowere efficacy was observed in the acetylated derivatives (-N-CO-R/COOH), further dercease in efficacy in this group of compounds was obserced with increasing R size up to 2 carbon atoms. No clear toxicity was observed for all the tested compounds for the following parameters: haematological (11b, PCV, RBC2, MC11, MCV and MCHC), brochemical (serum GOT, total protein, Uric acid, Na, K, Ca, Fe, Cu, Co, Mg, Mn) and histopathological. All the compounds have been fourn to possess weak antimicrobial activity when tested in PRG and PEG against the four standard bacterial microorganisms: B. SUBTILIS, S. AUREUS, E. COLI, P. AERUGINOSA and the two fungal organisms: S. CEREVISIAE AND C. ALBICANS. In the sulphonamide series of compounds, the higher activity was obtained when both the primary aromatic amino (Nup4) and the carboxyl groups were not derivatized. IN VIVO biocyclization of compounds-NH/-COOH (OLF-PZQ), -N-Co-CH3/-COOH (1), N-CH2CH3/-COOCH2CH3 (V11) and -N-CHsup2Chsup3/COOH (V111) (Figure 2.1) to praziquantel, has been investigated in a healthy bovans type chicks using TLC. No praziquantel or its hydroxy metabolites were detected.