- Structure-based discovery of 1H-indole-2-carboxamide derivatives as potent ASK1 inhibitors for potential treatment of ulcerative colitis
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Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) family, is implicated in many human diseases. Here, we describe the structural optimization of hit compound 7 and conduct further structure-activity relationship (SAR) studies that result in the development of compound 19 with a novel indole-2-carboxamide hinge scaffold. Compound 19 displays potent anti-ASK1 kinase activity and stronger inhibitory effect on ASK1 in AP1-HEK293 cells than previously described ASK1 inhibitor GS-4997. Besides improved in vitro activity, compound 19 also exhibits an appropriate in vivo PK profile. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 19 shows significant anti-UC efficacy and markedly attenuates DSS-induced body weight loss, colonic shortening, elevation in disease activity index (DAI) and inflammatory cell infiltration in colon tissues. Mechanistically, compound 19 represses the phosphorylation of ASK1-p38/JNK signaling pathways and suppresses the overexpression of inflammatory cytokines. Together, these findings suggest that ASK1 inhibitors can potentially be used as a therapeutic strategy for UC.
- Hou, Shaohua,Yang, Xiping,Tong, Yu,Yang, Yuejing,Chen, Quanwei,Wan, Boheng,Wei, Ran,Wang, Yuchen,Zhang, Yanmin,Kong, Bo,Huang, Jianhang,Chen, Yadong,Lu, Tao,Hu, Qinghua,Du, Ding
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- Discovery of Potent Succinate-Ubiquinone Oxidoreductase Inhibitors via Pharmacophore-linked Fragment Virtual Screening Approach
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Succinate-ubiquinone oxidoreductase (SQR) is an attractive target for fungicide discovery. Herein, we report the discovery of novel SQR inhibitors using a pharmacophore-linked fragment virtual screening approach, a new drug design method developed in our laboratory. Among newly designed compounds, compound 9s was identified as the most potent inhibitor with a Ki value of 34 nM against porcine SQR, displaying approximately 10-fold higher potency than that of the commercial control penthiopyrad. Further inhibitory kinetics studies revealed that compound 9s is a noncompetitive inhibitor with respect to the substrate cytochrome c and DCIP. Interestingly, compounds 8a, 9h, 9j, and 9k exhibited good in vivo preventive effects against Rhizoctonia solani. The results obtained from molecular modeling showed that the orientation of the R2 group had a significant effect on binding with the protein.
- Xiong, Li,Zhu, Xiao-Lei,Gao, Hua-Wei,Fu, Yu,Hu, Sheng-Quan,Jiang, Li-Na,Yang, Wen-Chao,Yang, Guang-Fu
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p. 4830 - 4837
(2016/07/06)
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- Design, synthesis and biological evaluation of 7-nitro-1H-indole-2- carboxylic acid derivatives as allosteric inhibitors of fructose-1,6- bisphosphatase
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A series of novel indole derivatives was synthesized as inhibitors of fructose-1,6-bisphosphatase (FBPase). Extensive structure-activity relationships were conducted and led to a potent FBPase inhibitor 3.9 with an IC50 of 0.99 μM. The binding mode of this series of indoles was predicted using CDOCKER algorithm. The results of this research will shed light on the further design and optimization of novel small molecules as FBPase inhibitors.
- Bie, Jianbo,Liu, Shuainan,Zhou, Jie,Xu, Bailing,Shen, Zhufang
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p. 1850 - 1862
(2014/03/21)
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- Indoles via Knoevenagel-Hemetsberger reaction sequence
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A series of substituted indoles have been synthesized by the sequential reaction of aromatic aldehydes with ethyl azidoacetate in the presence of sodium ethoxide to form the corresponding ethyl α-azido-β-arylacrylates (Knoevenagel process) followed by a solvent mediated thermolysis (Hemetsberger process). The isolated yields of the ethyl α-azido-β-arylacrylates were significantly increased when employing the sacrificial electrophile ethyl trifluoroacetate. 1H NMR and coupled 1H-13C NMR analysis of the ethyl α-azido-β-arylacrylates indicate that the condensation is stereospecific - only the Z-isomer could be detected. Solvent mediated thermal treatment of the meta-substituted ethyl α-azido-β- arylacrylates resulted in the formation of both the 5- and 7- substituted indoles - the 5-regioisomer being slightly favored over the 7-regioisomer. Analogous thermal treatment of (2Z, 2Z′)-diethyl 3,3′-(1,3- phenylene)bis(2-azidoacrylate) and (2Z, 2Z′)-diethyl 3,3′-(1,4- phenylene)bis(2-azidoacrylate) exclusively produced pyrroloindoles, diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate and diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate, respectively. Results are also reported which indicate that the α-azido-β-arylacrylates can be used in the subsequent Hemetsberger indolization process without prior purification.
- Heaner Iv, William L.,Gelbaum, Carol S.,Gelbaum, Leslie,Pollet, Pamela,Richman, Kent W.,Dubay, William,Butler, Jeffrey D.,Wells, Gregory,Liotta, Charles L.
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p. 13232 - 13242
(2013/09/02)
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- Efficient synthesis of 2-ethoxycarbonyl indoles
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An efficient one-pot procedure for the synthesis of 2-ethoxycarbonyl indoles from commercially available materials has been developed. The one-step procedure involves in situ formation of the hydrazones from phenylhydrazine hydrochloride and ethyl pyruvate in the presence of bismuth nitrate followed by Fischer cyclization in polyphosphoric acid and ethanol. This method is efficient and simple.
- Sudhakara,Jayadevappa,Mahadevan,Hulikal, Vijaykumar
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experimental part
p. 2506 - 2515
(2009/12/06)
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