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

Miyuki Kumazawa; Manabu Tejima; Miwa Fukuda; Shota Takeda; Kenji Suzuki; Yukiko Mizumoto; Kakeru Sato; Minoru Waki; Hiroyuki Miyachi; Akira Asai; Osamu Takikawa; Tomoko Hashimoto; Osamu Ohno; Kenji Matsuno

doi:10.1021/acsmedchemlett.0c00527

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

ACS Med Chem Lett. 2021 Jan 15;12(2):211-216. doi: 10.1021/acsmedchemlett.0c00527. eCollection 2021 Feb 11.

Authors

Affiliations

¹ Laboratory 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.
² Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
³ Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
⁴ National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, 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.