Quantitative Structure−Activity Relationships of 2,4-Diamino-5-(2-X-benzyl)pyrimidines versus Bacterial and Avian Dihydrofolate Reductase

• Published in: Journal of medicinal chemistry Vol. 41; no. 22; pp. 4261 - 4272
• Main Authors: Selassie, Cynthia Dias, Gan, Wei-Xi, Kallander, Lara S, Klein, Teri E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.10.1998; Amer Chemical Soc
• Subjects: 2,4-diamino-5-(2-X-benzyl)pyrimidines; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Aves; Biological and medical sciences; Chemistry, Medicinal; Chickens; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - chemistry; Folic Acid Antagonists - metabolism; Folic Acid Antagonists - pharmacology; Lactobacillus casei; Lactobacillus casei - enzymology; Life Sciences & Biomedicine; Liver - enzymology; Medical sciences; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Science & Technology; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase - metabolism; TRIMETHOPRIM; 2,4-DIAMINO-5-BENZYLPYRIMIDINES; COMPLEXES; DRUG DESIGN; DYNAMICS; ANTIBACTERIAL AGENTS; CRYSTAL; INHIBITOR BINDING; DERIVATIVES; Lactobacillus casei; Enzyme; Nitrogen heterocycle; Enzyme inhibitor; Modeling; Vertebrata; Structure activity relation; Benzylic compound; Animal; Molecular model; Bacteria; Lactobacillaceae; Pyrimidine derivatives; Chicken; Oxidoreductases; Dihydrofolate reductase; Aves; Antibacterial agent; Physicochemical properties
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970776j

Quantitative structure−activity relationships (QSAR) have been formulated for a set of 15 2,4-diamino-5-(2-X-benzyl)pyrimidines versus dihydrofolate reductase from Lactobacillus casei and chicken liver. QSARs were also developed for comprehensive data sets containing mono-, di-, and trisubstituted benzyl derivatives. Particular emphasis was placed on the role played by ortho substituents in the overall binding process and subsequent inhibition of the catalytic process in both the prokaryotic and eucaryotic DHFRs. Comparisons between the two QSARs reveal subtle differences at specific positions which can be optimized to design more selective antibacterial agents.