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New Antifolate 4,4′‐Diaminodiphenyl Sulfone Substituted 2,4‐Diamino‐5‐benzylpyrimidines. Proof of Their Dual Mode of Action and Autosynergism
Author(s) -
Wiese Michael,
Schmalz Dietmar,
Seydel Joachim K.
Publication year - 1996
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19963290309
Subject(s) - dihydrofolate reductase , antifolate , chemistry , sulfone , stereochemistry , enzyme , escherichia coli , biochemistry , antimetabolite , organic chemistry , toxicity , gene
New 4,4′‐diaminodiphenylsulfone substituted 2,4‐diamino‐5‐benzylpyrimidines were synthesized. These compounds are highly active inhibitors of both bacterial dihydrofolate reductase (DHFR) and dihydropteroic acid synthase (SYN). The simultaneous inhibition of both enzymes leads to autosynergism in whole cells in the same way as known for combinations of sulfonamides with trimethoprim. The inhibitory activity is demonstrated in cell‐free systems of DHFR and SYN derived from various species ( M. lufu, E. coli, C. albicans ) and in whole cell systems of the mycobacterial strain M. lufu. The compounds are rare examples for the combination of two mechanisms of action in one molecule.