Synthesis, evaluation and absolute configuration assignment of novel dihydropyrimidin-2-ones as picomolar sodium iodide symporter inhibitors

A small library of dihydropyrimidin-2-ones (DHPMs) was synthesized and evaluated for their potency to block iodide entrapment in rat thyroid cells. Synthesis was achieved using the multicomponent Biginelli reaction. Twelve compounds were tested for the inhibition of sodium iodide symporter (NIS) in a cell-based assay. One newly synthesized derivative exhibited a remarkably strong activity, with a half-maximum inhibitory concentration value (IC50) of 65 pM. Three DHPMs were further resolved from racemates using chiral HPLC and absolute configurations were assigned using circular dichroism spectroscopy. Biological evaluation showed that most of the activity against NIS resides in one enantiomer. This study provides new insights for the development of anti-thyroid drugs, as well as for the synthesis of novel pharmacological tools designed to investigate iodide transport mechanisms at cellular and molecular levels.

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► A targeted library of dihydropyrimidones was synthesized.
► Compounds were evaluated for inhibition of iodide entrapment in rat thyroid cells.
► New lead was identified with an IC50 value of 65 pM.
► Absolute configuration of three active derivatives was assigned.
► Biological activity is concentrated in one enantiomer.