Syntheses and Antiproliferative Evaluation of 6-Thienyl, 6-Polyphenyl Aryl and 6-Naphthyl Derivatives of 2,4-Diaminopyrido [3,2-d] pyramidine as Non-classical Antifolate Targeting DHFR

A series of 6-thienylethenyl, 6-polyphenyl arylethenyl, 6-thienylethyl and 6-polyphenyl arylethyl deriva- tives of 2,4-diaminopyrido[3,2-d]pyrimidine for targeting dihydrofolate reductase（DHFR） was designed and synthe- sized as non-classical antifolates in order to overcome drug resistance. The compounds were evaluated for in vitro antitumor activities, rhDHFR and antimicrobial activities. All the compounds exhibited antitumor activities, with ICs0 values in the range of 0.13--17.8 gmol/L against HL-60, HeLa and A549. Both the types of aryl groups and the orientation of polyphenyl aryl made an impact on the biological activities. 6-Naphthylethyl derivatives 5c and 5d were proved to be the most active Dt-IFR inhibitors, which were more potent than 6-phenylethyl, 6-thienylethyl and 6-biphenylethyl derivatives. Docking studies reveal that flexible saturated carbon-carbon bond of C9--C10 is essential for biological activities in molecular backbone. Antimicrobial test shows that most of the compounds exhibit antibacterial activities.