A series of new derivatives of dipyrimido[4,5-b:5,4-e][1,4] thiazine were synthesized by treatment of 5-amino-6-methyl-2-morpholino-4-pyrimidinethiol (1) with 5-bromo-2,4-dichloro-6-methylpyrimidine (2) in the presence of triethylamine and ethanol and subsequently with various secondary amines in EtOH/DMF. The thioether derivative 3 and heterocyclization products 4a–f were characterized by elemental analysis and spectroscopic techniques. The 15-LO inhibitory activities of the new synthesized compounds were also evaluated. The results show that compound 4e has the best IC50 of 15-LO inhibition (IC50 = 14.4 μM) but when all the products were theoretically docked into 15-LO, the GOLD scores of compounds 4e and 4d are 43.67 and 43.39 respectively, which show the best results. We suggest that the hydrogen bond interaction between Ser489 of 15-LO and the nitrogen of piperazine ring of compound 4e appears to play major role in lipoxygenase inhibition.

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