title: Synthesis of a new antischistosomally active and toxicologically tolerant C-12 monothione surrogate of the universal antihelmintic praziquantel.
abstract: A new C-12 monothione mimic (III) of the universal antihelmintic Praziquantel (I) namely, 2-cyclohexylthiocarbonyl( 1,2.3,6,7,11b)-hexahydro-4H-pyrazino[2-1a] isoquinoline-4-one was chemically synthesized and structurally elucidated (Elemental analysis. El-Mass, 13C-NMR and IR spectroscopy). Antischistosomal potency in the order of -76% comparable to that for our newly reported C-12 and C-4 dithion mimic II (-70%) and Praziquantel. Praziquantel (100%, mice infected with S. mansoni cercariae), was realized. Toxicological evaluation (mice liver and kidney functions) and biochemical parameters (cholesterol, triglycerides, albumin, total serum proteins and amino acid profile of liver protein homogenate) were also assayed. Comparable to the parent drug, general insignificant toxicological diferences could be attributed for III. Interestingly, III exhibited intermediate biological figures between I and II. An order of II<III<I with respect to the antischistosomal potency and II>III>I, for the other tested biochemical parameters was observed. A consideration of obtained results could indicate that, structurally, an intact glycine amide segment of the pyrazine moiety, as it is the case in both I and III, and not in II (glycine thioamide) seemed now more crucial for exhibiting an optimum antihelmintic potency as well as a more tolerant toxicity characteristics. Additionally, the obtained comparable amino acid profile of mice liver protein homogenate after the treatment by III, could suggest similar biochemical, lethal mechanistic and metabolic routes for II, III and I. The new lipophilic candidatee III seems to merit more profound chemical, biological, and pharmaceutical investigations.
authors.affiliation: National Research Center, Cairo, Egypt.
authors.forename: M H
authors.initials: MH
authors.lastname: Abo-Ghalia
authors.forename: A M
authors.initials: AM
authors.lastname: Soliman
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D011223:Praziquantel / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D012547:Schistosoma / Q000187:drug effects*; D012552:Schistosomiasis / Q000188:drug therapy; D012556:Schistosomicides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000871:Anthelmintics; D012556:Schistosomicides; D011223:Praziquantel