Investigation of aryl halides as ketone bioisosteres: Refinement of potent and selective inhibitors of human cytochrome P450 19A1 (aromatase)

Bioisosteric replacement of cyclic ketone functionality with aryl halides was investigated on a centrally-flexible, five-component 1,2,3-triazole-containing pharmacophore, resulting in enhanced inhibition of aromatase (CYP450 19A1). Structure–activity data generated from both syn- and anti-aldol precursors provides significant insights into the requirements for enhanced potency, validating this novel ketone-to-aryl halide bioisostere hypothesis.

Graphical abstractBioisosteric replacement of cyclic ketone functionality with aryl halides was investigated on a centrally-flexible, five-component 1,2,3-triazole-containing pharmacophore, resulting in enhanced inhibition of aromatase (CYP450 19A1). Structure–activity data generated from both syn- and anti-aldol precursors provides significant insights into the requirements for enhanced potency, validating the ketone-to-aryl halide bioisostere hypothesis.Figure optionsDownload full-size imageDownload as PowerPoint slide