STRUCTURAL STUDIES ON BIOACTIVE COMPOUNDS .28. SELECTIVE ACTIVITY OF TRIAZENYL-SUBSTITUTED PYRIMETHAMINE DERIVATIVES AGAINST PNEUMOCYSTIS-CARINII DIHYDROFOLATE-REDUCTASE

Triazenyl-substituted pyrimethamine derivatives 10a-s have been prepar ed by coupling diazotized 2,4-diamino-5-(3-amino-4-chlorophenyl)6-ethy l pyrimidine (1c) with a series of secondary amines in aqueous sodium carbonate solution. The triazenes which are stable and poorly soluble as free bases form more soluble, but unstable, salts with alkanesulfon ic acids. The lead dimethyltriazene 5-[4-chloro-3-(3,3-dimethyltriazen -1-yl)phenyl]-6- ethylpyrimidine (4a) forms a crystalline ethanesulfon ic acid salt (solvated with 2-propanol), which is protonated at the py rimidine N-1 position as determined by X-ray crystallography. The abil ity of these new triazenes to inhibit Pneumocystis carinii dihydrofola te reductase in vitro has been compared to that of triazene 4a. The mo st potent and selective compound, -[3-[3-[2-(acetyloxy)ethyl]-3-benzyl triazen-1-yl]- 4-chlorophenyl]-6-ethylpyrimidine (14a), has an IC50 va lue of 0.17 mu M against the microbial enzyme and potentially useful s electivity (rat liver IC50/P. carinii IC50 = 114).