M. Wiese et al., NEW ANTIFOLATE 4,4'-DIAMINODIPHENYL SULFONE SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINES - PROOF OF THEIR DUAL-MODE OF ACTION AND AUTOSYNERGISM, Archiv der pharmazie, 329(3), 1996, pp. 161-168
New 4,4'-diaminodiphenylsulfone substituted 2,4-diamino-5-benzylpyrimi
dines were synthesized. These compounds are highly active inhibitors O
f both bacterial dihydrofolate reductase (DHFR) and dihydropteroic aci
d synthase (SYN). The simultaneous inhibition of both enzymes leads to
autosynergism in whole cells in the same way as known for combination
s of sulfonamides with trimethoprim. The inhibitory activity is demons
trated in cell-free systems of DHFR and SYN derived from various speci
es (M. lufu, E. coli, C. albicans) and in whole cell systems of the my
cobacterial strain M. lufu. The compounds are rare examples for the co
mbination of two mechanisms of action in one molecule.