Novel Chemical Method for Decreasing of Toxicity of Highly Cytotoxic Amidoximes by Introduction of Benzo[4,5]imidazo[2,1-b]thiazolyl Fragment

Abstract

Aims and Objectives: The aim of the research is to obtain and to investigate the cytotoxicity of a novel class of non-toxic oximes – derivatives of N-(benzo[4,5]imidazo[2,1-b]thiazol-3-ylmethoxy)-ω- (hetarylsulfanyl)-alkanamidines. Materials and Methods: To assess the possible toxicity of the compounds, acute oral LD50 was calculated. The calculations were based on tested compounds IC50 values in relation to 3T3 (mouse fibroblast cell line) using NRU assay. Monolayer tumor cell lines HT-1080 (human fibrosarcoma, ATCC® CCL-121™), MH-22A (mouse hepatoma, ECACC code, 96121721) and NIH/3T3 (mouse Swiss Albino embryo fibroblasts, ATCC® CRL-1658™), were cultured in standard medium (Dulbecco`s modified Eagle`s medium) supplemented with 10% fetal bovine serum (“Sigma”). Results: E-Stereoselective synthesis of novel N-(benzo[4,5]imidazo[2,1-b]thiazol-3-ylmethoxy)-ω- (hetarylsulfanyl)alkanamidines as potential cytotoxic agents was carried out in three steps from corresponding thiones. N-(Benzo[4,5]imidazo[2,1-b]thiazol-3-ylmethoxy)-5-(benzothiazol-2-ylsulfanyl)-pentanamidine exhibits high activity in vitro on the monolayer tumour cell lines: MG-22A (mouse hepatoma) and HT-1080 (human fibrosarcoma). Besides this, the above compound exhibits low toxicity on the 3T3 cell line and low estimated acute oral LD50 (LD50 2759 mg/kg). Conclusion: In conclusion, such dramatic decreasing of expected acute toxicity and high cytotoxicity by the introduction of benzo[4,5]imidazo[2,1-b]thiazolyl fragment into N-hydroxy-ω-(hetarylsulfanyl)alkanamidines were demonstrated for the first time (see, for example, toxicity and cytotoxicity of compound 8b and corresponding unsubstituted oxime).