Synthesis and Antitumor Activity of Heterocycles Related to Carbendazim: Synthesis and Antitumor Activity of Heterocycles Related to Carbendazim

Three types of compounds were synthesized from carbendazim (1), a benzimidazole derivative (Scheme). They included a group of esters at N1 prepared by treating carbendazim with isocyanates bearing ester groups (2a, 2b, 2c), carboxyalkyl-1,2,3,4-tetrahydro-s-triazino[1,2-a]benzimidazole-2,4-dione esters (3a and 3b, 3d and 3c derived from 3a. The antitumor potencies of the N1 esters were in the range of 7 to 40M, which compares favorably with carbendazim, but their water solubilities were low. The s-triazine derivatives showed activity against pancreatic tumor cells, and one of them (3b) was active in mice, but they were not effective against other tumor types. Treatment of carbendazim with 3-bromopropionyl chloride produced 1-methoxycarbonyl-4-oxo-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (4), which gave 1-(3-aminopropionyl)benzimidazole 2-methylcarbamates, substituted on the amino nitrogen (5a, 5b, and 5d), when treated with amines. These products showed some antitumor activity in cell cultures, and an ethoxy derivative (5c), obtained by treating 1-methoxycarbonyl-4-oxo-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole with sodium ethoxide, was active in the 67-150M range. Some of the new compounds had good water solubility. Carbendazim kills tumor cells by inhibiting tubulin; however, s-triazine 3b, which differs from it in size and functional groups, does not act by this mechanism.