2,4-Diamino-5-benzylpyrimidines and analogs as antibacterial agents. 11. Quinolylmethyl analogs with basic substituents conveying specificity

• Published in: Journal of medicinal chemistry Vol. 32; no. 8; pp. 1936 - 1942
• Main Authors: Davis, Steven E, Rauckman, Barbara S, Chan, Joseph H, Roth, Barbara
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.08.1989
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Chemical Phenomena; Chemistry; Escherichia coli; Escherichia coli - enzymology; Folic Acid Antagonists; Liver - enzymology; Microbial Sensitivity Tests; Neisseria gonorrhoeae - enzymology; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Quinolines - chemical synthesis; Quinolines - pharmacology; Rats; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00128a041

A series of nine 2,4-diamino-5-[6-( or 7-)quinolylmethyl]pyrimidines has been prepared by condensations of quinolinecarboxaldehydes with beta-anilinopropionitriles, followed by treatment with guanidine. All compounds has basic or methoxy substituents at the 2- or 4-positions of the quinoline ring. All of the 6-quinolylmethyl derivatives were highly inhibitory against Escherichia coli dihydrofolate reductase (DHFR), provided that an 8-substituent was present in the quinoline ring. Those compounds that had basic substituents in the 2-position of the quinoline ring were also highly specific for bacterial dihydrofolate DHFR, relative to a vertebrate counterpart. Protonation on the quinoline ring nitrogen is a possible cause of specificity.