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Discovery of hybrids of indolin-2-one and nitroimidazole as potent inhibitors against drug-resistant bacteria

Abstract

With antibiotics resistance developing rapidly, new antibacterial agents are needed to be discovered. We readily synthesized 11 indolin-2-one compounds and found a hybrid of indolin-2-one and nitroimidazole 3-((1-methyl-5-nitro-1H-imidazol-2-yl)methylene)indolin-2-one to be effective on Staphylococcus aureus strains. Six derivatives of this compound were further designed and synthesized in order to enhance its efficacy. After a second turn of structural refinement, a novel hybrid of indolin-2-one and nitroimidazole 3-((1-methyl-5-nitro-1H-imidazol-2-yl)methylene)-5-nitroindolin-2-one with a nitro group on C-5 position of indolin-2-one was shown to exhibit remarkable antibacterial activities with a low MIC value against MRSA ATCC 33591. Besides, this molecule demonstrated its potency on Gram-negative bacteria and VRE strain. The time-killing curve experiment showed its good bactericidal activity. Low hemolytic rate suggested its promising safety profile.

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Acknowledgments

This work was financially supported by grants from the National Natural Science Foundation of China (Grant NO. 81602956 and 81473253), National Major Program of China during the 13th Five-Year Plan Period (Grant NO. 2018ZX09721001-001-001), and China Postdoctoral Science Foundation (Grant NO. 2016M590895). Thank Sichuan Provincial People’s Hospital for the supply of VRE B148 strains.

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Correspondence to Tao Yang or Youfu Luo.

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