Nonclassical 2,4-Diamino-6-(aminomethyl)-5,6,7,8-tetrahydroquinazoline Antifolates: Synthesis and Biological Activities

Aleem Gangjee, Nurulain Zaveri, Mohit Kothare, Sherry F. Queener

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22 Scopus citations

Abstract

Twenty 6-substituted 2,4-diaminotetrahydroquinazolines were designed, synthesized, and biologically evaluated as novel nonclassical inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents. The 6-substituents included substituted anilinomethyls, with alkoxy (OCH3 and OCH2CH3) and halogen (Cl and Br) moieties on the phenyl ring; an indolinomethyl; and 1-naphthylaminomethyls. The compounds were synthesized from a protected key intermediate 2,4-bis(acetamido)-5,6,7,8-tetrahydroquinazoline-6-carboxaldehyde (26) by reductive amination with the appropriate amine. Compound 26 was obtained via a Diels-Alder reaction of 2-(trimethylsiloxy)-1,3-butadiene with acrolein to afford cyclohexanone-4-carboxaldehyde dimethyl acetal (23) after deprotection of the silyloxy group and protection of the aldehyde in a single step. Cyclocondensation of 23 with dicyandiamide followed by protection of the 2,4-diamino groups and deprotection of the 6-acetal gave 26. The compounds were significantly potent ((7-330) × 10-9 M) and selective against T. gondii (versus rat liver DHFR). The most selective analogue against T. gondii DHFR was 2,4-diamino-6-[[(2′,5′-dimethoxyphenyl)methylamino]methyl]-5,6,7,8- tetrahydroquinazoline (5) which showed exceptionally high inhibitory activity against the growth of T. gondii cells in culture (IC50 = 5.4 × 10-8 M). Selected analogues were evaluated as inhibitors of the growth of tumor cells in culture. The most active analogues inhibited the growth of tumor cells at GI50 = 10-8 M.

Original languageEnglish (US)
Pages (from-to)3660-3668
Number of pages9
JournalJournal of Medicinal Chemistry
Volume38
Issue number18
DOIs
StatePublished - Sep 1 1995

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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