2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 14. 2,3-Dihydro-1-(2,4-diamino-5-pyrimidyl)-1H-indenes as conformationally restricted analogs of trimethoprim

• Published in: Journal of medicinal chemistry Vol. 34; no. 2; pp. 550 - 555
• Main Authors: Chan, Joseph H, Roth, Barbara
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.02.1991
• Subjects: Animals; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - pharmacology; Chemical Phenomena; Chemistry; Escherichia coli; Folic Acid Antagonists; Rats; Stereoisomerism; Structure-Activity Relationship; Trimethoprim - analogs & derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00106a011

A conformationally restricted analogue of trimethoprim (1a) has been prepared by connecting the ortho position of the benzene ring to the methylene linkage with two methylene groups, thus forming a dihydroindene derivative (2b). The chemistry involved the condensation of barbituric acid with an indanone derivative, followed by a three-step conversion to a 2,4-diaminopyrimidine. The S isomer of 2b was found to have a minimum-energy conformation very similar to that of 1a when bound to Escherichia coli dihydrofolate reductase, in contrast to that of 1a in vertebrate DHFR. Theoretically such a derivative might have increased specificity and activity against the bacterial enzyme. Molecular modeling experiments suggested that the actual decreased activity was due to crowding in the enzyme, caused by the extra atoms needed to restrict the conformation.