title: Conformationally restricted analogues of trimethoprim: 2,6-diamino-8-substituted purines as potential dihydrofolate reductase inhibitors from Pneumocystis carinii and Toxoplasma gondii.
abstract: Twenty-two 2,6-diamino-8-substituted purines (2-23) were synthesized, in which rotation around the two flexible bonds of trimethoprim (TMP), linking the pyrimidine ring to the side chain phenyl ring, was restricted by incorporation into a purine ring, in an attempt to increase the potency and selectivity of TMP against dihydrofolate reductase (DHFR) from the organisms that often cause fatal opportunistic infections in patients with AIDS, i.e., Pneumocystis carinii (pc) and Toxoplasma gondii (tg). The syntheses of analogues 2-20 were achieved via a one-pot reaction of 2,4,5,6-tetraaminopyrimidine and the appropriately substituted benzaldehyde or phenyl acetaldehyde, in acidic methoxyethanol. Analogues 21-23 were synthesized via nucleophilic displacement of 2,6-diamino-8-(chloromethyl)purine with the appropriate anilines or 2-naphthalenethiol. The compounds were evaluated as inhibitors of pcDHFR and tgDHFR with rat liver (rl) DHFR as the mammalian reference enzyme. Compound 11, the 3',4'-dichlorophenyl analogue, was as potent as TMP and had a selectivity ratio of 13 for pcDHFR, which ranked it as one of the three most selective inhibitors of pcDHFR (compared to rlDHFR) known to date. It also displayed a selectivity ratio of 38 for tgDHFR. None of the other analogues showed any improvement compared to TMP in potency or selectivity. In the preclinical in vitro screening program of the National Cancer Institute, compound 11 showed a GI50 of 10(-6) M for the inhibition of the growth of 17 tumor cell lines.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gangjee
authors.forename: A
authors.initials: A
authors.lastname: Vasudevan
authors.forename: S F
authors.initials: SF
authors.lastname: Queener
mesh_terms: D017088:AIDS-Related Opportunistic Infections; D000818:Animals; D001665:Binding Sites; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008322:Mammals; D008968:Molecular Conformation; D011010:Pneumocystis / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014122:Toxoplasma / Q000201:enzymology* / Q000254:growth & development; D014295:Trimethoprim / Q000031:analogs & derivatives*
chemical_list: D005493:Folic Acid Antagonists; D007202:Indicators and Reagents; D011687:Purines; D011743:Pyrimidines; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase