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Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

1
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
2
Department of Chemistry, Sogang University, Seoul 121-742, Korea
3
Korea Chemical Bank, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea
4
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea
5
Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2017, 22(11), 1936; https://doi.org/10.3390/molecules22111936
Received: 25 September 2017 / Revised: 8 November 2017 / Accepted: 8 November 2017 / Published: 9 November 2017
(This article belongs to the Section Medicinal Chemistry)
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that is highly overexpressed in various cancer cells and antigen-presenting cells. It has emerged as an attractive therapeutic target for cancer immunotherapy, which has prompted high interest in the development of small-molecule inhibitors. To discover novel IDO1 inhibitors, we designed and synthesized a series of N′-hydroxyindazolecarboximidamides. Among the compounds synthesized, compound 8a inhibited both tryptophan depletion and kynurenine production through the IDO1 enzyme. Molecular docking studies revealed that 8a binds to IDO1 with the same binding mode as the analog, epacadostat (INCB24360). Here, we report the synthesis and biological evaluation of these hydroxyindazolecarboximidamides and present the molecular docking study of 8a with IDO1. View Full-Text
Keywords: indoleamine 2,3-dioxygenase 1; N’-hydroxyindazolecarboximidamide; cancer immunotherapy; tryptophan depletion; kynurenine production indoleamine 2,3-dioxygenase 1; N’-hydroxyindazolecarboximidamide; cancer immunotherapy; tryptophan depletion; kynurenine production
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MDPI and ACS Style

Lee, D.-H.; Lee, J.-Y.; Jeong, J.; Kim, M.; Lee, K.W.; Jang, E.; Ahn, S.; Lee, C.H.; Hwang, J.Y. Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors. Molecules 2017, 22, 1936. https://doi.org/10.3390/molecules22111936

AMA Style

Lee D-H, Lee J-Y, Jeong J, Kim M, Lee KW, Jang E, Ahn S, Lee CH, Hwang JY. Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors. Molecules. 2017; 22(11):1936. https://doi.org/10.3390/molecules22111936

Chicago/Turabian Style

Lee, Dong-Ho; Lee, Joo-Youn; Jeong, Jieun; Kim, Miok; Lee, Kyung W.; Jang, Eunseo; Ahn, Sunjoo; Lee, Chang H.; Hwang, Jong Y. 2017. "Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors" Molecules 22, no. 11: 1936. https://doi.org/10.3390/molecules22111936

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