Conformationally restricted analogues of trimethoprim: 2,6-diamino-8- substituted purines as potential dihydrofolate reductase inhibitors from Pneumocystis carinii and Toxoplasma gondii

Aleem Gangjee, Anil Vasudevan, Sherry F. Queener

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3032-3039
Number of pages8
JournalJournal of Medicinal Chemistry
Volume40
Issue number19
DOIs
StatePublished - Sep 26 1997

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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