2,4-Diamino-5-benzylpyrimidines and analogs as antibacterial agents. 11. Quinolylmethyl analogs 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. A...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1989-08, Vol.32 (8), p.1936-1942
Main Authors: Davis, Steven E, Rauckman, Barbara S, Chan, Joseph H, Roth, Barbara
Format: Article
Language:English
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00128a041