Synthesis and Biological Evaluation of Dithiobisacetamides as Novel Urease Inhibitors |
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Authors: | Mei-Ling Liu Wei-Yi Li Hai-Lian Fang Ya-Xi Ye Su-Ya Li Wan-Qing Song Prof. Zhu-Ping Xiao Prof. Hui Ouyang Prof. Hai-Liang Zhu |
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Affiliation: | 1. Hunan Provincial Key Laboratory of Research, Resource Mining and High-valued Utilization on Edible & Medicinal Plant, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, National Demonstration Center for Experimental Chemistry Education, Jishou University, The South Section of Renmin Road 120, Jishou, China;2. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Xianlin Road 163, Nanjing, China |
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Abstract: | Thirty-eight disulfides containing N-arylacetamide were designed and synthesized in an effort to develop novel urease inhibitors. Biological evaluation revealed that some of the synthetic compounds exhibited strong inhibitory potency against both cell-free urease and urease in intact cell with low cytotoxicity to mammalian cells even at concentration up to 250 μM. Of note, 2,2′-dithiobis(N-(2-fluorophenyl)acetamide) ( d7 ), 2,2′-dithiobis(N-(3,5-difluorophenyl)acetamide) ( d24 ), and 2,2′-dithiobis(N-(3-fluorophenyl)acetamide) ( d8 ) were here identified as the most active inhibitors with IC50 of 0.074, 0.44, and 0.81 μM, showing 32- to 355-fold higher potency than the positive control acetohydroxamic acid. These disulfides were confirmed to bind urease without covalent modification of the cysteine residue and to inhibit urease reversibly with a mixed inhibition mechanism. They also showed very good anti-Helicobacter pylori activities with d8 showing a comparable potency to the clinical used drug amoxicillin. The impressive in vitro biological profile indicated their immense potential as therapeutic agents to tackle H. pylori caused infections. |
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Keywords: | Dithiobisacetamide reversible urease inhibitor Helicobacter pylori cytotoxicity. |
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