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Design and structural optimization of novel 2H-benzo[h]chromene derivatives that target AcrB and reverse bacterial multidrug resistance
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-11-27 , DOI: 10.1016/j.ejmech.2020.113049
Yinhu Wang , Rawaf Alenazy , Xinjie Gu , Steven W. Polyak , Panpan Zhang , Matthew J. Sykes , Na Zhang , Henrietta Venter , Shutao Ma

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, inhibit 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 π-π stacking interactions and hydrogen bond networks were the major contributors to tight binding of AcrB.



中文翻译:

设计和结构优化针对AcrB和反向细菌多药耐药性的新型2 H-苯并[h]色烯衍生物

鉴于其在促进多药耐药性中的关键作用,药物外排泵已成为治疗细菌感染的新药物靶标。本文中,通过整合分子设计和基于结构的药效团模型设计了新型的苯并二氢吡喃酮和2 H-苯并[h]色烯衍生物,以试图鉴定针对大肠杆菌AcrB的改良外排泵抑制剂。测试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。鉴定出二十三种新颖结构,它们与经测试的抗菌素协同作用,抑制尼罗河红外排并特别作用于AcrB。其中,WK2WL7表现出广谱和高效外排抑制活性的WL10被确定为潜在的理想AcrB抑制剂。分子建模进一步揭示,强大的π-π堆积相互作用和氢键网络是AcrB紧密结合的主要因素。

更新日期:2020-11-27
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