Pyrrolo[2,3- d]pyrimidines and pyrido[2,3- d]pyrimidines as conformationally restricted analogues of the antibacterial agent trimethoprim

• Published in: Bioorganic & medicinal chemistry 1996-04, Vol.4 (4), p.593-602
• Main Authors: Kuyper, Lee F, Garvey, Janice M, Baccanari, David P, Champness, John N, Stammers, David K, Beddell, Christopher R
• Format: Article
• Language: English
• Subjects: Animals; Anti-Infective Agents, Urinary - chemistry; Binding Sites; Crystallography, X-Ray; Escherichia coli - enzymology; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - pharmacology; Humans; Hydrogen Bonding; Liver - enzymology; Molecular Conformation; Neisseria gonorrhoeae - enzymology; Plasmodium berghei - enzymology; Rats; Staphylococcus aureus - enzymology; Structure-Activity Relationship; Trimethoprim - analogs & derivatives; Trimethoprim - chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/0968-0896(96)00045-4

Conformationally restricted analogues of the antibacterial agent trimethoprim (TMP) were designed to mimic the conformation of drug observed in its complex with bacterial dihydrofolate reductase (DHFR). This conformation of TMP was achieved by linking the 4-amino function to the methylene group by one- and two-carbon bridges. A pyrrolo[2,3- d]pyrimidine, a dihydro analogue, and a tetrahydropyrido[2,3- d]pyrimidine were synthesized and tested as inhibitors of DHFR. One analogue showed activity equivalent to that of TMP against DHFR from three species of bacteria. An X-ray crystal structure of this inhibitor bound to Escherichia coli DHFR was determined to evaluate the structural consequences of the conformational restriction. Graphic