Article | Published:

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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Boucher HW, et al. Bad bugs, no drugs: no ESKAPE! an update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1–12.

  2. 2.

    Willyard C. The drug-resistant bacteria that pose the greatest health threats. Nature. 2017;543:15.

  3. 3.

    Kaur M, Singh M, Chadha N, Silakari O. Oxindole: a chemical prism carrying plethora of therapeutic benefits. Eur J Med Chem. 2016;123:858–94.

  4. 4.

    Rajesh Kumar M,Alagumuthu M,Violet Dhayabaran V, N-substituted hydroxynaphthalene imino-oxindole derivatives as new class of PI3-kinase inhibitor and breast cancer drug: molecular validation and structure-activity relationship studies. Chem Biol Drug Des. 2018;91:277–84.

  5. 5.

    Ho HK, et al. Benzylidene-indolinones are effective as multi-targeted kinase inhibitor therapeutics against hepatocellular carcinoma. Mol Oncol. 2014;8:1266–77.

  6. 6.

    Ji C, et al. Design, synthesis and biological evaluation of novel antitumor spirotetrahydrothiopyran–oxindole derivatives as potent p53-MDM2 inhibitors. Bioorg Med Chem. 2017;25:5268–77.

  7. 7.

    Romagnoli R, et al. Design, synthesis and biological evaluation of 3-substituted-2-oxindole hybrid derivatives as novel anticancer agents. Eur J Med Chem. 2017;134:258–70.

  8. 8.

    Ashraf Ali M, et al. AChE inhibitor: a regio- and stereo-selective 1,3-dipolar cycloaddition for the synthesis of novel substituted 5,6-dimethoxy spiro[5.3′]-oxindole-spiro-[6.3″]-2,3-dihydro-1H-inden-1″-one-7-(substituted aryl)-tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole. Bioorg Med Chem Lett. 2012;22:508–11.

  9. 9.

    Akrami H, et al. Indolinone-based acetylcholinesterase inhibitors: synthesis, biological activity and molecular modeling. Eur J Med Chem. 2014;84:375–81.

  10. 10.

    Sun Y, et al. One-step synthesis of chiral oxindole-type analogues with potent anti-inflammatory and analgesic activities. Sci Rep. 2015;5:13699.

  11. 11.

    Chen G,  et al. Synthesis and biological evaluation of novel indole-2-one and 7-aza-2-oxindole derivatives as anti-inflammatory agents. Drug Des Devel Ther. 2014; 8: 1869–92.

  12. 12.

    MIDOH N, et al. Antioxidative activities of oxindole-3-acetic acid derivatives from supersweet corn powder. Biosci Biotechnol Biochem. 2010;74:1794–801.

  13. 13.

    Ahmad I, et al. Xanthine oxidase/tyrosinase inhibiting, antioxidant, and antifungal oxindole alkaloids from Isatis costata. Pharm Biol. 2010;48:716–21.

  14. 14.

    Furuta K, Mizuno Y, Maeda M, Koyama H, Hirata Y. Synthesis of 3-arylmethyl-2-oxindole derivatives and their effects on neuronal cell death. Chem Pharm Bull. 2017;65:1093–7.

  15. 15.

    Furuta K, et al. Synthesis of 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole derivatives and their effects on neuronal cell death. Bioorg Med Chem Lett. 2017;27:4457–61.

  16. 16.

    Gholamzadeh P, Mohammadi Ziarani G, Badiei A, Abolhassani Soorki A, Lashgari N. Efficient green synthesis of isoindigo derivatives using sulfonic-acid-functionalized nanoporous silica (SBA-Pr-SO3H) catalyst and study of their antimicrobial properties. Res Chem Intermed. 2013;39:3925–36.

  17. 17.

    Hosseinzadeh N, et al. 5-Nitro-heteroarylidene analogs of 2-thiazolylimino-4-thiazolidinones as a novel series of antibacterial agents. Med Chem Res. 2013;22:2293–302.

  18. 18.

    Batista A, et al. Antimicrobial effects of violacein against planktonic cells and biofilms of Staphylococcus aureus. Molecules. 2017;22:1534.

  19. 19.

    Rindhe SS, Karale BK, Gupta RC, Rode MA. Synthesis, antimicrobial and antioxidant activity of some oxindoles. Indian J Pharm Sci. 2011;73:292–6.

  20. 20.

    Li M-C, et al. Four new minor brominated indole related alkaloids with antibacterial activities from Laurencia similis. Bioorg Med Chem Lett. 2016;26:3590–3.

  21. 21.

    Majik MS, Rodrigues C, Mascarenhas S, D’Souza L. Design and synthesis of marine natural product-based 1H-indole-2,3-dione scaffold as a new antifouling/antibacterial agent against fouling bacteria. Bioorg Chem. 2014;54:89–95.

  22. 22.

    Acharya AP, et al. Green method for synthesis of 3-[2-(substituted-phenyl)-2-oxo ethylidene]-1,3-dihydro-indol-2-one and their in vitro antimicrobial activity. Res Chem Intermed. 2015;41:2953–9.

  23. 23.

    Winkelmann E,Raether W,Gebert U,Sinharay A, Chemotherapeutically active nitro compounds. 4. 5-Nitroimidazoles (part I). Arzneimittelforschung. 1977;27:2251–63.

  24. 24.

    Ang CW, Jarrad AM, Cooper MA, Blaskovich MAT. Nitroimidazoles: molecular fireworks that combat a broad spectrum of infectious diseases. J Med Chem. 2017;60:7636–57.

Download references


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.

Author information

Correspondence to Tao Yang or Youfu Luo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supporting Information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading

Fig. 1
Scheme 1
Fig. 2
Scheme 2
Fig. 3
Fig. 4