An efficient one-pot synthesis of tethered cyclohexadiene enaminonitriles from methyl-ketones: an effective route to quinazolines.

Abstract

The quinazolines represent a useful natural product scaffold with demonstrated activities against disorders such as high blood pressure and benign prostatic hyperplasia. Here we report on the synthesis and biological activity of a series of quinazolines that were prepared by a one-pot synthesis of substituted cyclohexadiene enaminonitriles from methyl-ketones. The approach, which employs NaH, complements published procedures where LDA is utilized. While the NaH catalyzed reaction generates the cyclohexadiene enaminonitriles in high yields with heterocyclic substrates, the reaction fails to promote product formation of aliphatic alkyl substrates. On the contrary, the LDA mediated synthesis favors the long chain alkyl substituents while reactions involving the aromatic substrates result in low yields. The final conversion to the quinazolines is also a modification on literature protocols. In cellular assays, the quinazolines showed the most promising activity against Jurkat with CC(50) values in the low micromolar range. Weak activity was observed against microbial strains (Bacillus subtilis, Escherichia coli, and Saccharomyces cerevisiae). The substituted enaminonitrile intermediates also exhibited weak anti-microbial activity and cytotoxicity against human T-cell leukemia.

• Authors: Bennie J Bench, Victor H Suarez, Coran M H Watanabe
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 10 Pg. 3126-30 (May 15 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 17967539 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Infective Agents
• Cyclohexenes
• Ketones
• Nitriles
• Quinazolines
• 1,4-cyclohexadiene

Topics

• Anti-Infective Agents (chemical synthesis, chemistry)
• Bacteria (drug effects)
• Biochemistry (methods)
• Cyclohexenes (chemical synthesis, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• Jurkat Cells
• Ketones (chemistry)
• Microbial Sensitivity Tests
• Molecular Structure
• Nitriles (chemical synthesis, chemistry, pharmacology)
• Quinazolines (chemical synthesis, chemistry, pharmacology)