Synthesis and antitumour activity of trimethylsilylpropyl substituted benzimidazoles

The quaternisation of N-substituted benzimidazoles by heating with various alkyl, allyl, propargyl and benzyl chlorides and bromides leads to the form ation of benzimidazolinium salts. The interaction of N-monosubstituted benz imidazoles with various salts (CuCl2, ZnCl2, CoCl2, PdCl2, and AgNO3) Yield ed stable sol-id complexes. Potential cytotoxic activity of synthesised ben zimidazolinium salts and benzimidazole metal complexes was tested in vitro on four monolayer tumour cell Hues: MG-22A (mouse hepatoma), HT-1080 (human fibrosarcoma), B16 (mouse melanoma), Neuro 2A (mouse neuroblastoma) and no rmal mouse fibroblast cells. A preliminary analysis of the structure-activi ty relationship for the benzimidazole derivatives clearly indicates that th e character of substituents in the benzimidazole ring has strong influence on the cytotoxic activity. The insertion of the silicon atom into the N-alk yl chain increases the cytotoxic activity of benzimidazolinium salts signif icantly, which show a very significant potency in vitro against all studied tumour cell lines, being particularly active in experiments with B16 (mous e melanoma). TD, for the most active compounds are in the range 0.001-0.008 mug ml(-1). Cytotoxicity of benzimidazole metal complexes (L2MX2) strongly depends on the metal nature. 1-(3-Trimethylsilylpropyl)benzimidazole in do se 1 mg kg(-1) inhibits carcinoma S-180 tumour growth by 62% (on ICR mice). (C) 2001 Editions scientifiques et medicales Elsevier SAS.