title: 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 10. 2,4-Diamino-5-(6-quinolylmethyl)- and -[(tetrahydro-6-quinolyl)methyl]pyrimidine derivatives. Further specificity studies.
abstract: A series of 18 2,4-diamino-5-[(1,2,3,4-tetrahydro-6-quinolyl)methyl]pyrimidines has been prepared by the condensation of 2,4-diamino-5-(hydroxymethyl)pyrimidine with 1,2,3,4-tetrahydroquinolines in acidic medium. Several derivatives were catalytically aromatized; others were synthesized from these by routine aromatic substitution or by condensations of (anilinomethyl)pyrimidines to give quinolinylmethyl analogues. Compounds with 4-methyl-8-methoxy substitution are closely related to trimethoprim (1a) in structure and are excellent inhibitors of bacterial dihydrofolate reductase, with activity at least equivalent to that of 1a. The highest degree of inhibition was achieved with the rigid aromatic series, but greater specificity was accomplished among the tetrahydroquinoline derivatives. This was directly related to N-1 substitution of 4-methyl-8-methoxy derivatives. The spatial relationships around N-1 and protonation at this site may both affect selectivity. Such compounds also had excellent broad-spectrum in vitro antibacterial activity.
authors.affiliation: Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
authors.forename: B S
authors.initials: BS
authors.lastname: Rauckman
authors.forename: M Y
authors.initials: MY
authors.lastname: Tidwell
authors.forename: J V
authors.initials: JV
authors.lastname: Johnson
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; D004926:Escherichia coli / Q000201:enzymology; D005493:Folic Acid Antagonists; D008099:Liver / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000201:enzymology; 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