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Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors.

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.

SUBMITTER: Kumazawa M

PROVIDER: S-EPMC7883372 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors.

Kumazawa Miyuki M Tejima Manabu M Fukuda Miwa M Takeda Shota S Suzuki Kenji K Mizumoto Yukiko Y Sato Kakeru K Waki Minoru M Miyachi Hiroyuki H Asai Akira A Takikawa Osamu O Hashimoto Tomoko T Ohno Osamu O Matsuno Kenji K

ACS medicinal chemistry letters 20210115 2

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 a ...[more]

PMID: 33603967

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