title: New antifolate 4,4'-diaminodiphenyl sulfone substituted 2,4-diamino-5-benzylpyrimidines. Proof of their dual mode of action and autosynergism.
abstract: 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.
authors.affiliation: Forschungszentrum Borstel, Zentrum für Medizin und Biowissenschaften, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wiese
authors.forename: D
authors.initials: D
authors.lastname: Schmalz
authors.forename: J K
authors.initials: JK
authors.lastname: Seydel
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D003622:Dapsone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011743:Pyrimidines; C003361:SDDS; D003622:Dapsone; D004094:Dihydropteroate Synthase