Design and structural optimization of novel 2H-benzo[h]chromene derivatives that target AcrB and reverse bacterial multidrug resistance

Eur J Med Chem. 2021 Mar 5:213:113049. doi: 10.1016/j.ejmech.2020.113049.

Yinhu Wang ¹, Rawaf Alenazy ², Xinjie Gu ³, Steven W Polyak ⁴, Panpan Zhang ³, Matthew J Sykes ⁴, Na Zhang ³, Henrietta Venter ⁵, Shutao Ma ⁶

Affiliations

1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, 250012, China; School of Pharmacy, Liaocheng University, Liaocheng, China.
2 Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia; Department of Medical Laboratory, College of Applied Medical Sciences-Shaqra, Shaqra University, 11961, Saudi Arabia.
3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, 250012, China.
4 Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
5 Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia. Electronic address: [email protected].
6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, 250012, China. Electronic address: [email protected].

PMID: 33279291 DOI: 10.1016/j.ejmech.2020.113049

Abstract

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

Keywords

2H-benzo[h]chromene; AcrB inhibitors; Efflux inhibitory activity; Multidrug resistance.

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