Combinatorial mixture synthesis and biological evaluation of dihydrophenyltriazine antifolates

The traditional 'one-pot' three component synthesis was adapted successfull y for combinatorial mixtures synthesis of dihydrophenyl triazines, which ar e nonclassical, dihydrofolate reductase (DHFR) inhibitors. Each library was designed to comprise eight reaction mixture pots and in every pot there we re three dihydrophenyl triazines. A total of three libraries were synthesiz ed and the final number of compounds harvested was 64. The products precipi tated out of the reaction mixture and could be collected easily and cleanse d by washing. Solid supports and further purification processes were not re quired. The reactions were monitored by TLC and a HPLC method was developed to determine the number of products in each pot. All 24 pots were screened for inhibitory activity against the rat liver DHFR. Two pots showed good i nhibitory activity and the products in them were individually synthesized, characterized and biologically tested again. One lead compound was identifi ed amongst all the compounds synthesized, and would be further optimized. ( C) 1999 Elsevier Science Ltd. All rights reserved.