2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 11. Quinolylmethyl analogues with basic substituents conveying specificity.
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.
Davis
S E
SE
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
Rauckman
B S
BS
Chan
J H
JH
Roth
B
B
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
D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011804:Quinolines