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  3. Design and synthesis of benzochromene derivatives as AcrB inhibitors for the reversal of bacterial multidrug resistance

Design and synthesis of benzochromene derivatives as AcrB inhibitors for the reversal of bacterial multidrug resistance

  • Eur J Med Chem. 2023 Mar 5;249:115148. doi: 10.1016/j.ejmech.2023.115148.
Ting Guo 1,  Yang Chen 2,  Weijin Chen 1,  Susan J Semple 3,  Xiaotong Gu 1,  Steven W Polyak 2,  Guanglin Sun 1,  Henrietta Venter 4,  Shutao Ma 5
Affiliations

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.
  • 2 Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
  • 3 Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia.
  • 4 Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia. Electronic address: rietie.venter@unisa.edu.au.
  • 5 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: mashutao@sdu.edu.cn.
PMID: 36709649 DOI: 10.1016/j.ejmech.2023.115148
Abstract

A series of novel benzo[h]chromene compounds were designed, synthesized and evaluated for their biological activity as AcrB inhibitors. The compounds were assessed for their ability to potentiate the effect of Antibiotics. Compounds with antibiotic-potentiating effects were then evaluated for inhibition of Nile Red efflux, and for off-target effects including activity on the outer and inner Bacterial membranes and toxicity. Six compounds were identified to reduce the MIC values of at least one of the tested Antibiotics by at least 4-fold, and further reduced the MICs in the presence of a membrane permeabilizer. The identified compounds were also able to inhibit Nile Red efflux at concentrations between 50 μM and 200 μM. The compounds did not disrupt the Bacterial outer membrane nor display toxicity in a nematode model (Caenorhabditis elegans). The 4-methoxyphenoxy)propoxy derivative compound G6 possessed the most potent Antibacterial potentiation with erythromycin by 8-fold even without the presence of a membrane permeabilizer. Furthermore, H6, G6, G10 and G11 completely abolished the Nile Red efflux at a concentration of 50 μM. The 3,4-dihydro-2H-benzo[h]chromen-5-yl)(morpholino)methanone core appears to be a promising chemical skeleton to be further studied in the discovery of more putative AcrB inhibitors.

Keywords

AcrB; Antibacterial sensitizing activity; Benzo[h]chromene derivatives; Efflux pump inhibitor; Inhibition of efflux; Multidrug resistance.

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