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

Abstract

A series of 6-thienylethenyl, 6-polyphenyl arylethenyl, 6-thienylethyl and 6-polyphenyl arylethyl derivatives of 2,4-diaminopyrido[3,2-d]pyrimidine for targeting dihydrofolate reductase(DHFR) was designed and synthesized 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 IC₅₀ values in the range of 0.13―17.8 μmol/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 DHFR 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.

Keywords

Non-classical antifolate / Dihydrofolate reductase(DHFR) / Antitumor / Antimicrobial

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