Design and application of a rigid quinazolone scaffold based on two-face Bim α-helix mimicking

• We analysed a quinazolone scaffold which could mimic two faces of Bim α-helix.
• A rigid bicyclic ring was necessary for mimicking peptide amphipathic feature.
• 6c interacted with R263 and occupied two hydrophobic pockets of Mcl-1.
• Compound 6c exhibited nanomolar affinities toward Mcl-1/Bcl-2 protein.

Based on our previous discovery of an anthraquinone scaffold mimicking two faces of Bim α-helix, we derived a quinazolone scaffold through structure simplification and optimization. It was inferred that a rigid bicyclic ring was necessary and efficient to maintain the two-faced binding mode. A novel dual inhibitor 6c [6,7,8-trihydroxy-3-(2-hydroxy-5-methylbenzyl)-2-phenylquinazolin-4(3H)-one] was obtained based on this scaffold. 6c exhibited dual binding activity with Ki values of 0.123 μM for Mcl-1 and 0.179 μM for Bcl-2.

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