Nonclassical 2,4-diamino-6-(aminomethyl)-5,6,7,8-tetrahydroquinazoline antifolates: Synthesis and biological activities

Aleem Gangjee, Nurulain Zaveri, Mohit Kothare, Sherry Queener

Research output: Contribution to journalArticle

22 Citations (Scopus)

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
Pages (from-to)3660-3668
Number of pages9
JournalJournal of Medicinal Chemistry
Volume38
Issue number18
StatePublished - 1995

Fingerprint

Folic Acid Antagonists
Tetrahydrofolate Dehydrogenase
Toxoplasma
Bioactivity
Tumors
Cells
Acrolein
Amination
Acetals
Growth Inhibitors
Halogens
Cell culture
Aldehydes
Liver
Antineoplastic Agents
Amines
Rats
Cell Culture Techniques
Pneumocystis carinii
Cycloaddition Reaction

ASJC Scopus subject areas

  • Organic Chemistry

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Nonclassical 2,4-diamino-6-(aminomethyl)-5,6,7,8-tetrahydroquinazoline antifolates : Synthesis and biological activities. / Gangjee, Aleem; Zaveri, Nurulain; Kothare, Mohit; Queener, Sherry.

In: Journal of Medicinal Chemistry, Vol. 38, No. 18, 1995, p. 3660-3668.

Research output: Contribution to journalArticle

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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.",
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