Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors

• Main Authors: Xiu-juan Lan, Hai-tao Yan, Feng Lin, Shi Hou, Chen-chen Li, Guang-shu Wang, Wei Sun, Jun-hai Xiao, Song Li
• Format: Article
• Language: English
• Published: MDPI AG 2019-07-01
• Series: Molecules
• Subjects: Colistin resistance; virtual screening; MCR-1 inhibitors; 1-phenyl-2-(phenylamino) ethanone derivatives
• Online Access: https://www.mdpi.com/1420-3049/24/15/2719

Polymyxins are considered to be the last-line antibiotics that are used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria; however, the plasmid-mediated transferable colistin resistance gene (<i>mcr-1</i>) has rendered polymyxins ineffective. Therefore, the protein encoded by <i>mcr-1</i>, MCR-1, could be a target for structure-based design of inhibitors to tackle polymyxins resistance. Here, we identified racemic compound <b>3</b> as a potential MCR-1 inhibitor by virtual screening, and 26 compound <b>3</b> derivatives were synthesized and evaluated in vitro. In the cell-based assay, compound <b>6g</b>, <b>6h</b>, <b>6i</b>, <b>6n</b>, <b>6p</b>, <b>6q</b>, and <b>6r</b> displayed more potent activity than compound <b>3</b>. Notably, 25 &#956;&#924; of compound <b>6p</b> or <b>6q</b> combined with 2 &#956;g&#183;mL-1 colistin could completely inhibit the growth of BL21(DE3) expressing <i>mcr-1</i>, which exhibited the most potent activity. In the enzymatic assay, we elucidate that <b>6p</b> and <b>6q</b> could target the MCR-1 to inhibit the activity of the protein. Additionally, a molecular docking study showed that <b>6p</b> and <b>6q</b> could interact with Glu246 and Thr285 via hydrogen bonds and occupy well the cavity of the MCR-1 protein. These results may provide a potential avenue to overcome colistin resistance, and provide some valuable information for further investigation on MCR-1 inhibitors.