Synthesis of 2-amino-s-triazino[1,2-a]benzimidazoles as potential antifolates from 2-guanidino- and 2-guanidino-5-methylbenzimidazoles

Article abstract of DOI:10.1002/jhet.5570430115

The syntheses of 2-amino-s-triazino[1,2-a]benzimidazoles from 2-guanidinobenzimidazoles were successfully carried out by a ring annelation reaction. The regiochemistry of the ring closure of 5-methyl-2- guanidinobenzimidazole with diethyl azodicarboxylate, aldehydes, acetone, diethyl ethoxymethylene-malonate and orthoesters, leading to the formation of s-triazine ring was studied. High regioselectivity was not observed in any of these reactions. However, the synthesis of s-triazino[1,2-a]benzimidazole system was found to be more regioselective than its 3,4-dihydro analogue. NOESY experiment indicated that the compound, 2-amino-4,4-dimethyl-3,4-dihydro-s- triazino[1,2-a]benzimidazole existed predominantly as the 3,4-dihydro tautomer in dimethyl sulfoxide. It was found to inhibit bovine dihydrofolate reductase with IC₅₀ 10.9 μM.