Design and synthesis of azaisoflavone analogs as phytoestrogen mimetics

• A series of azaisoflavone analogs were designed and synthesized.
• Several compounds showed promising ER activity and subtype selectivity.
• Docking analysis provided insight into their different activities and selectivities.
• The active azaisoflavones showed biphasic effect on the MCF-7 cell growth.

A series of azaisoflavone analogs were designed and synthesized and their transactivation activities and binding affinities for ERα and ERβ were investigated. Among these compounds, 2b and 3a were the most potent with 6.5 and 1.1 μM of EC50, respectively. Molecular modeling study showed putative binding modes of the compound 3a in the active site of ERα and ERβ, which were similar with that of genistein and provided insight of the effect of N-alkyl substitution of azaisoflavones on ERβ activity. Also, a biphasic effect of azaisoflavone analogs on MCF-7 cell growth depending on their concentrations was investigated.

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