title: 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 12. 1,2-Dihydroquinolylmethyl analogues with high activity and specificity for bacterial dihydrofolate reductase.
abstract: Twelve 2,4-diamino-5-[(1,2-dihydro-6-quinolyl)methyl]pyrimidines containing gem-dimethyl or fluoromethyl substituents at the 2-position of the dihydroquinoline ring were prepared by condensations of dihydroquinolines with 2,4-diamino-5-(hydroxymethyl)pyrimidine. The dihydroquinolines were produced from the reaction of anilines with mesityl oxide or fluoroacetone. In some cases, 1-aryl-2,4-dimethylpyrroles were obtained as byproducts. Most of these pyrimidines were highly inhibitory to Escherichia coli dihydrofolate reductase (DHFR) and also had high specificity for the bacterial enzyme. 2,4-Diamino-5-[[1,2-dihydro-2,4-dimethyl-3-fluoro-2-(fluoromethyl)-8- methoxy-6(1H)quinolyl]methyl]pyrimidine had an apparent Ki value for E. coli DHFR 13 times lower than that of the control, trimethoprim (1), and was 1 order of magnitude more selective for the bacterial enzyme. It had outstanding activity against Gram-positive organisms in vitro, as well as broad-spectrum antibacterial activity equivalent to that of 1. The results of in vivo testing will be reported elsewhere. The gem-dimethyl substituents of the dihydroquinoline derivatives are considered to be responsible for the high selectivity, as well as contributing to potent bacterial DHFR inhibition. Molecular models are presented which suggest the probable interactions with the bacterial enzyme.
authors.affiliation: Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
authors.forename: J V
authors.initials: JV
authors.lastname: Johnson
authors.forename: B S
authors.initials: BS
authors.lastname: Rauchman
authors.forename: D P
authors.initials: DP
authors.lastname: Baccanari
authors.forename: B
authors.initials: B
authors.lastname: Roth
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D002645:Chickens; D004926:Escherichia coli / Q000201:enzymology; D005493:Folic Acid Antagonists; D008099:Liver / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011804:Quinolines