- 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
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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.
- Tu, Shun,Zhang, Ting-jian,Zhang, Yi,Zhang, Xu,Zhang, Zhen-hao,Meng, Fan-hao
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- Amide-based xanthine oxidase inhibitors bearing an N-(1-alkyl-3-cyano-1H-indol-5-yl) moiety: Design, synthesis and structure-activity relationship investigation
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Our previous work identified a promising isonicotinamide based xanthine oxidase (XO) inhibitor, N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (1), and concluded that amide is an effective linker in exploring the XO inhibitor chemical space that is completely different from the five-membered ring framework of febuxostat and topiroxostat. Indole, an endogenous bioactive substance and a popular drug construction fragment, was involved in the structural optimization campaign of the present effort. After the installation of some functional groups, N-(1-alkyl-3-cyano-1H-indol-5-yl) was generated and employed to mend the missing H-bond interaction between the 3′-cyano of 1 and Asn768 residue of XO by shortening their distance. In this context, eight kinds of heterocyclic aromatic amide chemotypes were rationally designed and synthesized to investigate the structure-activity relationship (SAR) of amide-based XO inhibitors. The optimized compound a6 (IC50 = 0.018 μM) exhibits 17.2-fold improved potency than the initial compound 1 (IC50 = 0.31 μM). Its potency is comparable to that of topiroxostat (IC50 = 0.013 μM). Molecular docking and molecular dynamics studies proved the existence of the stable H-bond between the cyano group and the Asn768 residue. Moreover, oral administration of a6 (11.8 mg/kg) could effectively reduce serum uric acid levels in an acute hyperuricemia rat model. Liver microsomal stability assay illustrated that compound a6 possesses well metabolic stability in rat liver microsomes. However, the in vivo potency of a6 was much lower than that of topiroxostat, which may be explained by the poor absorption found in the parallel artificial membrane permeability assay (PAMPA). In addition, 6a has non-cytotoxicity against normal cell lines MCF10A and 16HBE. Taken together, this work culminated in the identification of compound 6a as an excellent lead for further exploration of amide-based XO inhibitors.
- Zhang, Ting-jian,Tu, Shun,Zhang, Xu,Wang, Qiu-yin,Hu, Sen-sen,Zhang, Yi,Zhang, Zhen-hao,Wang, Zhao-ran,Meng, Fan-hao
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- 1-substituted-3-substituted-5-substituted amide-1H-indole compounds as well as preparation method and application thereof
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The invention belongs to the technical field of medicines, and particularly relates to 1-substituted-3-substituted-5-substitutedamide-1H-indole compounds as well as a preparation method and application thereof. The structural general formula I of the compounds is specifically shown in the specification. Pharmacological research shows that the compounds show a good effect in an in-vitro xanthine oxidase inhibitory activity test, and are free of obvious toxic and side effect. The preparation method of the 1-substituted-3-substituted-5-substituted amide-1H-indole compounds provided by the invention is simple and feasible, relatively high in yield and easy for large-scale production.
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Paragraph 0069; 0072-0073
(2020/05/14)
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