title: 2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 14. 2,3-Dihydro-1-(2,4-diamino-5-pyrimidyl)-1H-indenes as conformationally restricted analogues of trimethoprim.
abstract: 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.
authors.affiliation: Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
authors.forename: J H
authors.initials: JH
authors.lastname: Chan
authors.forename: B
authors.initials: B
authors.lastname: Roth
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D005493:Folic Acid Antagonists; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014295:Trimethoprim / Q000031:analogs & derivatives*
chemical_list: D000890:Anti-Infective Agents; D005493:Folic Acid Antagonists; D014295:Trimethoprim