6625-96-3Relevant articles and documents
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.
Trichloroisocyanuric acid (TCCA) and carboxamide interactions in TCCA/NaNO2 triggered nitration of pyrrole and indole in aqueous aprotic media: A kinetic correlation of solvent properties with reactivity
Duguta, Govardhan,Muddam, Bhooshan,Kamatala, Chinna Rajanna,Utkoor, Umesh Kumar
, p. 164 - 186 (2020/10/02)
This study deals with the trichloroisocyanuric acid (TCCA) interactions with carboxamides like formamide (FMA), N,N′-dimethyl formamide (DMF), and N,N′-dimethyl acetamide (DMA) interactions during the nitration of heterocyclic compounds (HC) like pyrrole and indole in the presence of excess of [NaNO2] over the concentrations of all other reactants. All the reactions were performed in aqueous acetonitrile media containing carboxamide under acid-free conditions. Kinetics of the reactions revealed first order in [nitrating agent] and [HC] under otherwise similar conditions. To gain an insight into the reactive species and role of added carboxamide (FAA, DMF, DMA, etc.), the observed rates of the nitration reaction (log k) were analyzed as a function of (1/D), ([D ? 1]/[2D + 1]), mole fraction (nx), and volume (%) of carboxamide, 1/viscosity, density refractive index function), and Hildebrand solubility parameter plots. Linear regression analysis gave very good correlation coefficients (R2 values), which indicate the importance of several solvent properties in addition to the role of dielectric constant (D) of the reaction media. Multiple linear solvent energy relationships suggested by Abraham, Koppel, Palm, and Taft also afforded very good correlation coefficient (R2 values), showing the importance of cumulative effect of solvent properties. Besides these features, the negative entropies of activation (?S#) suggest greater solvation in the transition state. Isokinetic temperature (β) values for different protocols were very close to the experimental temperature range (303-323 K), indicating the importance of both enthalpy and entropy factors in controlling the reaction.
N-(3-cyano-1H-indol-5-yl)isonicotinamide and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide derivatives: Novel amide-based xanthine oxidase inhibitors
Tu, Shun,Zhang, Ting-jian,Zhang, Yi,Zhang, Xu,Zhang, Zhen-hao,Meng, Fan-hao
, (2021/07/31)
Our previous work demonstrated that amide is an efficient linker to explore chemical space of xanthine oxidase (XO) inhibitors that are entirely different from febuxostat and topiroxostat. In this effort, with 3-cyano-1H-indol-5-yl as a key moiety, two series of amide-based XO inhibitors, N-(3-cyano-1H-indol-5-yl)isonicotinamides (2a-w) and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamides (3a-i), were designed and synthesized. The structure-activity relationship investigation identified N-(3-cyano-1-cyclopentyl-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (3i, IC50 = 0.62 μM) as the most promising compound, with 14.4-fold higher in vitro inhibitory potency than allopurinol (IC50 = 8.91 μM). Molecular simulations provided reasonable interaction modes for the representative compounds. Furthermore, in vivo activity evaluation demonstrated that compound 3i (oral dose of 12.8 mg/kg) has obviously hypouricemic effect on a potassium oxonate induced hyperuricemic rat model. Cytotoxicity assay and ADME prediction also supported that 3i is an excellent lead for further exploration of amide-based XO inhibitors.