10553-13-6Relevant articles and documents
Yudin et al.
, (1971)
Design, synthesis, and biological evaluation of N-(3-cyano-1H-indol-5/6-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamides and 5-(6-oxo-1,6-dihydropyrimidin-2-yl)-1H-indole-3-carbonitriles as novel xanthine oxidase inhibitors
Zhang, Bing,Duan, Yulin,Yang, Yuwei,Mao, Qing,Lin, Fengwei,Gao, Jun,Dai, Xiwen,Zhang, Peng,Li, Qiuhua,Li, Jinxin,Dai, Ronghua,Wang, Shaojie
, (2021/10/26)
Xanthine oxidase (XO) has been an important target for the treatment of hyperuricemia and gout. The analysis of potential interactions of pyrimidinone and 3-cyano indole pharmacophores present in the corresponding reported XO inhibitors with parts of the XO active pocket indicated that they both can be used as effective fragments for the fragment-based design of nonpurine XO inhibitors. In this paper, we adopted the fragment-based drug design strategy to link the two fragments with an amide bond to design the type 1 compounds 13a–13w,14c, 14d, 14f, 14g, 14j, 14k, and 15g. Compound 13g displayed an evident XO inhibitory potency (IC50 = 0.16 μM), which was 52.3-fold higher than that of allopurinol (IC50 = 8.37 μM). For comparison, type 2 compounds 5-(6-oxo-1,6-dihydropyrimidin-2-yl)-1H-indole-3-carbonitriles (25c–25g) were also designed by linking the two fragments with a single bond directly. The results showed that compound 25c from the latter series displayed the best inhibitory potency (IC50 = 0.085 μM), and it was 98.5-fold stronger than that of allopurinol (IC50 = 8.37 μM). These results suggested that amide and single bonds were applicable for linking the two fragments together to obtain potent nonpurine XO inhibitors. The structure–activity relationship results revealed that hydrophobic groups at N-atom of the indole moiety were indispensable for the improvement of the inhibitory potency in vitro against XO. In addition, enzyme kinetics studies suggested that compounds 13g and 25c, as the most promising XO inhibitors for the two types of target compounds, acted as mixed-type inhibitors for XO. Moreover, molecular modeling studies suggested that the pyrimidinone and indole moieties of the target compounds could interact well with key amino acid residues in the active pocket of XO. Furthermore, in vivo hypouricemic effect demonstrated that compounds 13g and 25c could effectively reduce serum uric acid levels at an oral dose of 10 mg/kg. Therefore, compounds 13g and 25c could be potential and efficacious agents for the treatment of hyperuricemia and gout.
2-(1H-INDOLE-3-CARBONYL)-THIAZOLE-4-CARBOXAMIDE DERIVATIVES AND RELATED COMPOUNDS AS ARYL HYDROCARBON RECEPTOR (AHR) AGONISTS FOR THE TREATMENT OF E.G. ANGIOGENESIS IMPLICATED OR INFLAMMATORY DISORDERS
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Paragraph 00162; 00364, (2021/06/26)
2-(1H-lndole-3-carbonyl)-thiazole-4-carboxamide derivatives and the corresponding imidazole, oxazole and thiophene derivatives and related compounds as aryl hydrocarbon receptor (AHR) agonists for the treatment of angiogenesis implicated disorders, such as e.g. retinopathy, psoriasis, rheumatoid arthritis, obesity and cancer, or inflammatory disorders. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 27 to 32 and 59 to 219; examples 1 to 8; compounds 1-1 to 1-97; tables 1-a, 2 and 3).
Iron-Catalyzed C3-Formylation of Indoles with Formaldehyde and Aqueous Ammonia under Air
Wang, Qing-Dong,Zhou, Bin,Yang, Jin-Ming,Fang, Dong,Ren, Jiangmeng,Zeng, Bu-Bing
supporting information, p. 2670 - 2674 (2017/10/06)
An efficient iron-catalyzed C3-selective formylation of free (N-H) or N-substituted indoles was developed by employing formaldehyde and aqueous ammonia, with air as the oxidant. This new method gave 3-formylindoles in moderate to excellent yields with fairly short reaction times. Moreover, this procedure for catalytic formylation of indoles can be applied to gram-scale syntheses.
