Design, synthesis and evaluation of a series of 5-methoxy-2,3-naphthalimide derivatives as AcrB inhibitors for the reversal of bacterial resistance

Chaobin Jin; Rawaf Alenazy; Yinhu Wang; Rumana Mowla; Yinhui Qin; Jin Quan Eugene Tan; Natansh Deepak Modi; Xinjie Gu; Steven W Polyak; Henrietta Venter; Shutao Ma

doi:10.1016/j.bmcl.2019.02.003

Design, synthesis and evaluation of a series of 5-methoxy-2,3-naphthalimide derivatives as AcrB inhibitors for the reversal of bacterial resistance

Bioorg Med Chem Lett. 2019 Apr 1;29(7):882-889. doi: 10.1016/j.bmcl.2019.02.003. Epub 2019 Feb 4.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China; Department of Medical Laboratory, College of Applied Medical Sciences - Shaqra, Shaqra University, 11961, Saudi Arabia.
² School of Pharmacy and Medical Sciences, University of South Australia, 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, Shandong University, 44 West Culture Road, Jinan 250012, China.
⁴ School of Pharmacy and Medical Sciences, University of South Australia, SA 5000, Australia.
⁵ School of Pharmacy and Medical Sciences, University of South Australia, SA 5000, Australia. Electronic address: rietie.venter@unisa.edu.au.
⁶ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address: mashutao@sdu.edu.cn.

PMID: 30755336
DOI: 10.1016/j.bmcl.2019.02.003

Abstract

A series of novel 5-methoxy-2,3-naphthalimide derivatives were designed, synthesized and evaluated for their biological activities. In particular, the ability of the compounds to synergize with antimicrobials, to inhibit Nile Red efflux, and to target AcrB was assayed. The results showed that the most of the tested compounds more sensitized the Escherichia coli BW25113 to the antibiotics than the parent compounds 7c and 15, which were able to inhibit Nile Red efflux. Significantly, compound A5 possessed the most potent antibacterial synergizing activity in combination with levofloxacin by 4 times and 16 times at the concentration of 8 and 16 µg/mL, respectively, whilst A5 could effectively abolish Nile Red efflux at 100 μM. Additionally, target effect of A5 was confirmed in the outer- or inner membrane permeabilization assays. Therefore, A5 is an excellent lead compound for further structural optimization.

Keywords: 5-Methoxy-2,3-naphthalimide; AcrB; Antimicrobial resistance; Efflux pump inhibitor; Inhibition of efflux; Synergism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology*
Drug Resistance, Bacterial / drug effects*
Escherichia coli / drug effects*
Escherichia coli Proteins / antagonists & inhibitors*
Gene Expression Regulation, Bacterial / drug effects
Molecular Structure
Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
Naphthalimides / chemical synthesis*
Naphthalimides / chemistry
Naphthalimides / pharmacology*
Structure-Activity Relationship

Substances

AcrB protein, E coli
Anti-Bacterial Agents
Escherichia coli Proteins
Multidrug Resistance-Associated Proteins
Naphthalimides