title: Discovery and preliminary structure-activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties.
abstract: Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50value of 5.3μM. The structure-activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development.
authors: Department of Pharmaceutical Engineering, Xihua University, Chengdu 610039, PR China. Electronic address: qians33@163.com.
authors: Shan
authors: S
authors: Qian
authors: Department of Chemistry, Xihua University, Chengdu 610039, PR China.
authors: Tao
authors: T
authors: He
authors: Department of Pharmaceutical Engineering, Xihua University, Chengdu 610039, PR China.
authors: Wei
authors: W
authors: Wang
authors: Department of Pharmaceutical Engineering, Xihua University, Chengdu 610039, PR China.
authors: Yanying
authors: Y
authors: He
authors: Department of Pharmaceutical Engineering, Xihua University, Chengdu 610039, PR China.
authors: Man
authors: M
authors: Zhang
authors: Department of Pharmaceutical Engineering, Xihua University, Chengdu 610039, PR China.
authors: Lingling
authors: L
authors: Yang
authors: Department of Pharmaceutical Engineering, Xihua University, Chengdu 610039, PR China.
authors: Guobo
authors: G
authors: Li
authors: Department of Chemistry, Xihua University, Chengdu 610039, PR China. Electronic address: zhouyuwang77@gmail.com.
authors: Zhouyu
authors: Z
authors: Wang
mesh_terms: D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D055808:Drug Discovery; D006418:Heme / Q000737:chemistry; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: C000622785:4-(((6-bromo-1H-indazol-4-yl)amino)methyl)phenol; D001596:Benzylamines; D007191:Indazoles; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D006418:Heme
keywords: 1H-Indazoles; Cancer immunotherapy; Indoleamine 2,3-dioxygenase 1 (IDO1); Rational drug design; Small-molecular inhibitors