Synthesis of Pyridotriazolopyrimidines as Antitumor Agents

2-Hydrazino-5,7-di-p-tolylpyrido[2,3-d]pyrimidin-4(3H)-one (4) was prepared and condensed with different aldehydes 5a, 5b, 5c, 5d, 5e, 5f, 5g to give the corresponding hydrazone derivatives 6a, 6b, 6c, 6d, 6e, 6f, 6g. Oxidative cyclization of the latter compounds 6a, 6b, 6c, 6d, 6e, 6f, 6g gave the corresponding pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones 7a, 7b, 7c, 7d, 7e, 7f, 7g. Furthermore, compound 4 reacted with benzoyl chloride, triethyl orthoformate, acetyl chloride, ethyl chloroformate, and carbon disulphide in alcoholic KOH solution to afford the corresponding pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidinones (7a, 8, 9, 10, 11). The reaction of thione 3 or its 2-methylthio derivative 16 with hydrazonoyl halides 12a, 12b, 12c, 12d, 12e, 12f, 12g, 12h, 12i, 12j, 12k, 12l, 12m yielded the corresponding pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidinones 15a, 15b, 15c, 15d, 15e, 15f, 15g, 15h, 15i, 15j, 15k, 15l, 15m. The structures of all the products were confirmed by elemental and spectral analyses (¹H NMR, ¹³C NMR, IR, and MS). In addition, the anticancer activity of 20 pyridotriazolopyrimidinones against two cancer cell lines namely MCF-7 and HepG2 was evaluated, and the results revealed that compounds 7d and 9 have promising activity, compared with doxorubicin, which used as standard reference drug.