Design, synthesis and bioevaluation of novel 6-(4-Hydroxypiperidino)naphthalen-2-ol-based potential Selective Estrogen Receptor Modulators for breast cancer

• In-silico docking studies were used to optimize the ligand structure.
• A few of the tested compounds emerged as potent cytotoxics for breast cancer cells.
• The most potent compound showed strong antagonistic effects against ERα.
• Representative compounds displayed drug-like pharmacokinetic and toxicity profiles.

In a study directed towards development of novel Selective Estrogen Receptor Modulators (SERMs), 1-(4-(2-(dialkylamino)ethoxy)benzyl)-6-(4-hydroxypiperidin-1-yl)-2-naphthol and corresponding aryl methyl ethers were synthesized and bioevaluated against the estrogen-responsive human MCF-7 breast cancer cell line. The phenolic analogs displayed little or no activity, but aryl methyl ether analogs showed significant cytotoxic potency. Also, representative compounds from the aryl methyl ether series showed significant binding and antagonistic activity against ERα. Two representative compounds were also evaluated for in vitro membrane permeability, plasma stability as well as in-vivo toxicity in mice. The compounds displayed well-acceptable drug-like in vitro membrane permeability as well as plasma stability and were well-tolerated in experimental mice at 300 mg/kg dose.

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