Abstract
Purpose: To synthesis a series of novel thiazolo pyrimidine derivatives and evaluate them in vitro for their safety and anthelmintic activity against E. multilocularis metacestodes using BALB/c mice.Methods: A new series of substituted amino thiazole, hydrazinothiazole and thiazolo pyrimidine derivatives (2-6) were synthesized by reaction of compound 1 with potassium isothiocyanate to give the corresponding compound 2, which was used as starting material. The physicochemical characterization of these derivatives was carried out by nuclear magnetic resonance spectroscopy (1HNMR) and mass spectroscopy (MS).The purity of the compounds was determined by elemental analysis. Safety and anthelminthic activity of the compounds against E. multilocularis metacestodes was evaluated in vitro by i) viability assessment and relative abundance of 14-3-3 mRNA determination in E. multilocularis metacestodes-suspensions treated with 2, 5 and 10 μM concentrations of each compound separately. ii) bioassay at 15 weeks post-inoculation of mice by E. multilocularis suspensions-treated with 30 μM albendazole (ABZ), 10 μM thiazolopyrimidine derivative 5 (TPYDa) and a combination of both. Liver functions of all mice were tested before mice sacrifice.Results: TPYDa emerged as the active anthelmintic compound of the series against E. multilocularis metacestodes viability (activity, 60 %) compared with ABZ (activity, 63 %). When TPYDa was combined with ABZ, the activity reached 86 %. No mortality was found and liver function was normal in all mice during the studies.Conclusion: The compound, TPYDa, can serve as a lead molecule for further development to a clinically useful novel class of anthelmintic agents.Keywords: Thiazolopyrimidine, Synthesis, Echinococcosis, Mice, Chemotherapy
Highlights
Hepatic echinococcosis is a life-threatening disease, mainly differentiated into alveolar and cystic forms, associated with Echinococcus multilocularis (E. multilocularis) and Echinococcus granulosus (E. granulosus) infection respectively
Some 14-3-3 proteins have been shown to be aberrantly expressed in tumor cells, acting either pro- or anti-tumorogenic and there are a number of similarities between cancer cells and some parasites, echinococcus [5]
As an extension of our ongoing studies, the objective of the present work is to synthesis a series of TPYD derivatives and evaluates them both in vitro and in vivo for their anthelmintic activities against experimental E. multilocularis metacestodes in mice
Summary
Hepatic echinococcosis is a life-threatening disease, mainly differentiated into alveolar and cystic forms, associated with Echinococcus multilocularis (E. multilocularis) and Echinococcus granulosus (E. granulosus) infection respectively. E. multilocularis forms multilocular metacestodes that exhibit growth and/or proliferation of metacestodes over a long period of time leads to the development of space-occupying lesions, causes organ dysfunction, and can occasionally lead to death [2] Benzimidazole carbamate derivatives such as albendazole and mebendazole are currently the drugs of choice. Some 14-3-3 proteins have been shown to be aberrantly expressed in tumor cells, acting either pro- or anti-tumorogenic and there are a number of similarities between cancer cells and some parasites, echinococcus [5] Similarities include features such as the essentiality unlimited proliferative capacity of protoscoleces/brood capsules, the potential to modulate the immune response, the secretion of proteolytic enzymes to reach their target sites or organs, and the formation of metastases [6]. When echinoccocus 14-3-3 sequences are aligned in metacestodes group with the tumor-growth related zeta-isoforms of neoplastic mammalian cells [7]
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