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

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 muM: 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-chloroplienyl 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 muM, rat liver DHFR IC50/P. Carinii DHFR IC50: 5.26) was the most potent and the only P. varinii-selective antifolate of the new series. (C) 2002 Elsevier Science Ltd. All rights reserved.