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Novel 2-Substituted 3-Hydroxy-1,6-dimethylpyridin-4(1H)-ones as Dual-Acting Biofilm Inhibitors of Pseudomonas aeruginosa.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-31 , DOI: 10.1021/acs.jmedchem.0c00763 Jun Liu 1 , Jin-Song Hou 1 , Yi-Bin Li 1 , Zhi-Ying Miao 1 , Ping-Hua Sun 1 , Jing Lin 1 , Wei-Min Chen 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-31 , DOI: 10.1021/acs.jmedchem.0c00763 Jun Liu 1 , Jin-Song Hou 1 , Yi-Bin Li 1 , Zhi-Ying Miao 1 , Ping-Hua Sun 1 , Jing Lin 1 , Wei-Min Chen 1
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2-Heptyl-3-hydroxy-4(1H)-quinolone (PQS), a compound from P. aeruginosa, functions as both a quorum sensing (QS) regulator and a potent iron chelator to induce expression of pyoverdine and pyochelin which are involved in high-affinity iron transport systems. A potential dual-acting antibiofilm strategy requires molecules designed to interfere with iron uptake and the QS system of P. aeruginosa. A series of 2-substituted 3-hydroxy-1,6-dimethylpyridin-4-ones have been designed, synthesized, and tested as biofilm inhibitors of P. aeruginosa. One compound, N-((1,3,6-trimethyl-4-oxo-1,4-dihydropyridin-2-yl)methyl)hexanamide (10d), exhibits 68.67% biofilm inhibitory activity at 20 μM. Further mechanistic studies have confirmed that this compound not only inhibits the QS systems of P. aeruginosa but also acts as an iron chelator to compete strongly with pyoverdine, causing iron deficiency in bacteria. The pyoverdine receptor FpvA was revealed as the target of 10d by the Pvds mutant strain, fpvA-overexpressed strain, and in silico studies.
中文翻译：
新型2-取代的3-羟基-1,6-二甲基吡啶-4（1H）-作为铜绿假单胞菌的双重作用生物膜抑制剂。
铜绿假单胞菌的化合物2-Heptyl-3-hydroxy-4（1 H）-quinolone（PQS）既是群体感应（QS）调节剂，又是有效的铁螯合剂，可诱导pyoverdine和Pyochelin的表达。参与高亲和力铁运输系统。潜在的双重作用抗生物膜策略需要设计用于干扰铁摄取和铜绿假单胞菌QS系统的分子。已经设计，合成并测试了一系列2-取代的3-羟基-1,6-二甲基吡啶-4-酮作为铜绿假单胞菌的生物膜抑制剂。一种化合物，N -（（1,3,6-三甲基-4-氧代-1,4-二氢吡啶-2-基）甲基）己酰胺（10d）在20μM下表现出68.67％的生物膜抑制活性。进一步的机理研究已经证实，该化合物不仅抑制铜绿假单胞菌的QS系统，而且还充当铁螯合剂，与吡over定竞争激烈，从而导致细菌中铁缺乏。所述pyoverdine受体FPVA揭示作为目标10D由PVDS突变株，FPVA -overexpressed应变，和在计算机芯片上的研究。
更新日期：2020-10-08
中文翻译：
新型2-取代的3-羟基-1,6-二甲基吡啶-4（1H）-作为铜绿假单胞菌的双重作用生物膜抑制剂。
铜绿假单胞菌的化合物2-Heptyl-3-hydroxy-4（1 H）-quinolone（PQS）既是群体感应（QS）调节剂，又是有效的铁螯合剂，可诱导pyoverdine和Pyochelin的表达。参与高亲和力铁运输系统。潜在的双重作用抗生物膜策略需要设计用于干扰铁摄取和铜绿假单胞菌QS系统的分子。已经设计，合成并测试了一系列2-取代的3-羟基-1,6-二甲基吡啶-4-酮作为铜绿假单胞菌的生物膜抑制剂。一种化合物，N -（（1,3,6-三甲基-4-氧代-1,4-二氢吡啶-2-基）甲基）己酰胺（10d）在20μM下表现出68.67％的生物膜抑制活性。进一步的机理研究已经证实，该化合物不仅抑制铜绿假单胞菌的QS系统，而且还充当铁螯合剂，与吡over定竞争激烈，从而导致细菌中铁缺乏。所述pyoverdine受体FPVA揭示作为目标10D由PVDS突变株，FPVA -overexpressed应变，和在计算机芯片上的研究。
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