- 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.
- Paul, Saurav,Roy, Ashalata,Deka, Suman Jyoti,Panda, Subhankar,Trivedi, Vishal,Manna, Debasis
-
p. 364 - 375
(2016/06/13)
-
- Design and synthesis of N-methylpyrimidone derivatives as HIV-1 integrase inhibitors
-
A series of novel β-diketo derivatives which combined the virtues of dihydroxypyrimidine carboxamide derived from the evolution of DKA and polyhydroxylated aromatics moieties, were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and
- Wang, Yujie,Rong, Jie,Zhang, Bin,Hu, Liming,Wang, Xiaoli,Zeng, Chengchu
-
p. 735 - 741
(2015/02/19)
-
- RNase H active site inhibitors of human immunodeficiency virus type 1 reverse transcriptase: Design, biochemical activity, and structural information
-
Pyrimidinol carboxylic acids were designed as inhibitors of HIV-1 RNase H function. These molecules can coordinate to two divalent metal ions in the RNase H active site. Inhibition of enzymatic activity was measured in a biochemical assay, but no antivira
- Kirschberg, Thorsten A.,Balakrishnan, Mini,Squires, Neil H.,Barnes, Tiffany,Brendza, Katherine M.,Chen, Xiaowu,Eisenberg, Eugene J.,Jin, Weili,Kutty, Nilima,Leavitt, Stephanie,Liclican, Albert,Liu, Qi,Liu, Xiaohong,Mak, John,Perry, Jason K.,Wang, Michael,Watkins, William J.,Lansdon, Eric B.
-
supporting information; experimental part
p. 5781 - 5784
(2010/03/24)
-
- Discovery of potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70
-
A series of 1,2,4-oxadiazole analogues has been shown to be potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70, a potential therapeutic target for immune suppression. These compounds typically are 200- 400-fold more potent than the native,
- Vu, Chi B.,Corpuz, Evelyn G.,Merry, Taylor J.,Pradeepan, Selvaluxmi G.,Bartlett, Catherine,Bohacek, Regine S.,Botfield, Martyn C.,Eyermann, Charles J.,Lynch, Berkley A.,MacNeil, Ian A.,Ram, Mary K.,Van Schravendijk, Marie Rose,Violette, Shelia,Sawyer, Tomi K.
-
p. 4088 - 4098
(2007/10/03)
-
- Substituted phenyl-amidines
-
The present invention provides compounds of the formula: STR1 in which A is CH2, CHOH, CH2 O, CH2 S, CH2 NH, OCH2, SCH2, NH, NHCH2, NHCOCH2 or CH2 NHCH2, X1 is H, halogen, C1 -C4 -alkyl or C1 -C4 -alkoxy, X2 is halogen, C1 -C4 -alkyl or C1 -C4 -alkoxy, Z is 2-pyrimidinyl or C(=NR1)NHR2 (where R1 is H and R2 is H, OH or CH2 CO2 Et, or R1 and R2 together form CH2 CH2, CH2 CH2 CH2 or N=N), and their addition salts. The compounds of formula I and their salts are useful in therapy as hypotensive agents.
- -
-
-
