Synthesis of triazoloquinazolinone based compounds as tubulin polymerization inhibitors and vascular disrupting agents

• 1-phenyl-triazoloquinazolinone is considered as a conformationally restricted CA-4 analogue.
• A 3-hydroxy-4-methoxyphenyl group and N-methyl substitution are essentials for activity.
• Compound 12d displays potent anti-tubulin, cytotoxic and anti-vascular activities.

A series of 1-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-ones designed as conformationally restricted CA-4 analogues, were tested for their tubulin polymerization and growth inhibitory activities. The 3-hydroxy-4-methoxy derivatives 11d and 12d are potent inhibitors of tubulin assembly but only the N-methylated amid counterpart 12d possesses potent anticancer activity in a large panel of cancer cell lines. Upon treatment with compound 12d, remarkable cell shape changes as cell migration and tube formation were elicited in HUVECs, consistent with vasculature damaging activity.

The synthesis of new 1-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-one derivatives along with their tubulin polymerization inhibitory, anti-proliferative and anti-vascular activities is reported.Figure optionsDownload as PowerPoint slide