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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design and structural optimization of novel 2H-benzo[h]chromene derivatives that target AcrB and reverse bacterial multidrug resistance
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Design and structural optimization of novel 2H-benzo[h]chromene derivatives that target AcrB and reverse bacterial multidrug resistance

机译：新型2H-苯并[H]铬衍生物的设计与结构优化，靶向ACRB和逆细菌多药耐药性

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Drug efflux pumps have emerged as a new drug targets for the treatment of bacterial infections in view of its critical role in promoting multidrug resistance. Herein, novel chromanone and 2H-benzo[h]chromene derivatives were designed by means of integrated molecular design and structure-based pharmacophore modeling in an attempt to identify improved efflux pump inhibitors that target Escherichia coli AcrB. The compounds were tested for their efflux inhibitory activity, ability to inhibit efflux, and the effect on bacterial outer and inner membranes. Twenty-three novel structures were identified that synergized with antibacterials tested, inhibited Nile Red efflux, and acted specifically on the AcrB. Among them, WK2, WL7 and WL10 exhibiting broad-spectrum and high-efficiency efflux inhibitory activity were identified as potential ideal AcrB inhibitors. Molecular modeling further revealed that the strong pi-pi stacking interactions and hydrogen bond networks were the major contributors to tight binding of AcrB. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：鉴于药物外排泵在促进多药耐药性方面的关键作用，它已成为治疗细菌感染的新药物靶点。在此，通过集成的分子设计和基于结构的药效团建模，设计了新的色满酮和2H苯并[h]色烯衍生物，试图识别针对大肠杆菌AcrB的改进的外排泵抑制剂。测试了这些化合物的外排抑制活性、抑制外排的能力以及对细菌外膜和内膜的影响。共鉴定出23种新结构，它们与受试抗菌药物协同作用，抑制尼罗红外流，并对AcrB产生特异性作用。其中，具有广谱高效外排抑制活性的WK2、WL7和WL10被认为是潜在的理想AcrB抑制剂。分子模拟进一步揭示了强π-π堆积相互作用和氢键网络是导致AcrB紧密结合的主要因素。（C） 2020年爱思唯尔马森SAS。版权所有。

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