Structural studies on bioactive compounds. Part 36: Design, synthesis and biological evaluation of pyrimethamine-based antifolates against Pneumocystis carinii

Article abstract of DOI:10.1016/S0968-0896(02)00128-1

As part of a research effort to improve the quality of current chemotherapy of Pneumocystis carinii pneumonia, we report a structure-based design project to optimise activity, species selectivity and pharmaceutical properties of the triazenyl-pyrimethamine TAB (4) (IC₅₀=0.17 μM; rat liver DHFR IC₅₀/P. carinii DHFR IC₅₀=114). This has led us to design, synthesise and evaluate four new series of pyrimethamine derivatives bearing triazole, triazolium, triazinium and amino moieties at the 3′-position of the p-chlorophenyl ring. Such stabilised `triazene' derivatives address the potentially compromised pharmaceutical profile of TAB and the 3′-amine substituted agents afford conformationally flexible substitutes. The benzylamino-pyrimethamine derivative (24a) (IC₅₀=0.12 μM, rat liver DHFR IC₅₀/P. carinii DHFR IC₅₀: 5.26) was the most potent and the only P. carinii-selective antifolate of the new series.