Nitrobenzofurazan derivatives of N'-hydroxyamidines as potent inhibitors of indoleamine-2,3-dioxygenase 1.
Tryptophan metabolism through the kynurenine pathway is considered as a crucial mechanism in immune tolerance. Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in tryptophan catabolism in the immune system and it is also considered as an important therapeutic target for the treatment of cancer and other diseases that are linked with kynurenine pathway. In this study, a series of nitrobenzofurazan derivatives of N'-hydroxybenzimidamides (1) and N'-hydroxy-2-phenylacetimidamides (2) were synthesized and their inhibitory activities against human IDO1 enzyme were tested using in-vitro and cellular enzyme activity assay. The optimization leads to the identification of potent compounds, 1d, 2i and 2k (IC50 = 39-80 nM), which are either competitive or uncompetitive inhibitors of IDO1 enzyme. These compounds also showed IDO1 inhibition potencies in the nanomolar range (IC50 = 50-71 nM) in MDA-MB-231 cells with no/negligible amount of cytotoxicity. The stronger selectivity of the potent compounds for IDO1 enzyme over tryptophan 2,3-dioxygenase (TDO) enzyme (312-1593-fold) also makes them very attractive for further immunotherapeutic applications.
Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India.
Saurav
S
Paul
Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India.
Ashalata
A
Roy
Department of Bioscience and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India.
Suman Jyoti
SJ
Deka
Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India.
Subhankar
S
Panda
Department of Bioscience and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India.
Vishal
V
Trivedi
Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India. Electronic address: dmanna@iitg.ernet.in.
Debasis
D
Manna
D000578:Amidines / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010069:Oxadiazoles / Q000737:chemistry*; D011487:Protein Conformation
D000578:Amidines; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010069:Oxadiazoles; C014701:nitrobenzofuroxan
High selectivity; IDO1 inhibition; Low cytotoxicity; Mechanism-based drug design; N′-hydroxyamidines