Structural Studies on Bioactive Compounds. Part 36: Design, Synthesis and Biological Evaluation of Pyrimethamine-Based Antifolates Against Pneumocystis carinii Original Research Article

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 ‘triazeneʹ 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.