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) (IC(50)=0.17 microM; rat liver DHFR IC(50)/P. carinii DHFR IC(50)=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) (IC(50)=0.12 microM, rat liver DHFR IC(50)/P. carinii DHFR IC(50): 5.26) was the most potent and the only P. carinii-selective antifolate of the new series.
Chan
David C M
DC
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
Laughton
Charles A
CA
Queener
Sherry F
SF
Stevens
Malcolm F G
MF
D000818:Animals; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D009162:Mycobacterium avium / Q000201:enzymology; D011010:Pneumocystis / Q000201:enzymology*; D011739:Pyrimethamine / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects*; D014122:Toxoplasma / Q000201:enzymology; D014227:Triazines
D005493:Folic Acid Antagonists; D014227:Triazines; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine