Synthesis, in vitro and in vivo cytotoxicity, and prediction of the intestinal absorption of substituted 2-ethoxycarbonyl-imidazo[2,1-b]benzothiazoles

The imidazobenzothiazole compounds 3-17 together with the imidazobenzoxazol e 18, and the imidazobenzoimidazole 19 were prepared and their cytotoxic ac tivity evaluated at the National Cancer Institute (NCI) for testing against a panel of approximately 60 tumor cell lines. Compounds 5, 7, 8, and 16 ex hibited interesting in vitro cytotoxic activity. The most active imidazoben zothiazole derivative 8 was further evaluated as a cytotoxic agent in the h ollow fiber assay and showed a score greater than the minimum values for xe nograft testing together with a net cell kill. Comparison with the results displayed in the in vivo assay by standard antitumor drugs in clinical use revealed a significant in vivo activity of the benzothiazole compound. COMP ARE analyses for compounds 4-19 against the NCI's standard agent database s how poor or no correlation, and it might suggest for these compounds a mech anism of action unrelated to that of any known drug. Furthermore. the benzo thiazole 8 did not show significant antitumor activity in a panel of two xe notransplanted tumors (i.e. colon and non-small cell lung tumors). By compu ting the polar surface area of compounds 3-19 with the MAREA computer progr am it was established that the most active compounds 5, 7, 8, and 16 should experience good intestinal permeability. (C) 2001 Elsevier Science B.V. Al l rights reserved.