Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors
Miyuki Kumazawa1, Manabu Tejima1, Miwa Fukuda2
1Laboratory of Medicinal Chemistry, Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, 2665-1 Nakano-machi, Hachi-oji, Tokyo 192-0015, Japan.
Abstract:
A structure-activity relationship study unexpectedly showed that carbonothioates 4a and 4b, obtained by a unique alkaline hydrolysis of 2-alkylthio-oxazolines 3a and 3b, respectively, are a novel scaffold for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Derivatization of the carbonothioates enhanced inhibitory activity against IDO1 and cellular kynurenine production without cytotoxicity and led to the discovery of the related scaffolds carbonodithioates 5 and cyanocarbonimidodithioates 6 as IDO1 inhibitors. Incorporation of an OH group provided the most potent analogue 5i. UV-visible absorption spectroscopy of the Soret band, as well as docking and peptide mapping studies, suggested that these molecules bind to the heme in the active site of IDO1. Our unique IDO1 inhibitors are potential leads for future development.
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