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Synthesis of 2‐amino‐ s ‐triazino[1,2‐ a ]benzimidazoles as potential antifolates from 2‐guanidino‐ and 2‐guanidino‐5‐methylbenzimidazoles
Author(s) -
Dolzhenko Anton V.,
Chui WaiKeung
Publication year - 2006
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570430115
Subject(s) - chemistry , stereochemistry , combinatorial chemistry
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 ethoxymethylenemalonate 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 IC 50 10.9 μM.