Design, synthesis, and In vitro antituberculosis activity of 2(5H)-Furanone derivatives

IUBMB Life. 2016 Aug;68(8):612-20. doi: 10.1002/iub.1526. Epub 2016 Jun 27.


A series of 2(5H)-furanone-based compounds were synthesized from commercially available mucohalic acids. From the first-generation compounds, three showed inhibitory activity (10 µg/mL) of at least 35% against Mycobacterium smegmatis mc(2) 155 growth (Bioscreen C system). In screening the active first-generation compounds for growth inhibition against Mycobacterium tuberculosis H37Rv, the most active compound was identified with a minimum inhibitory concentration (MIC99 ) of 8.07 µg/mL (15.8 µM) using BACTEC 460 system. No cross-resistance was observed with some current first-line anti-TB drugs, since it similarly inhibited the growth of multidrug resistant (MDR) clinical isolates. The compound showed a good selectivity for mycobacteria since it did not inhibit the growth of selected Gram-positive and Gram-negative bacteria. It also showed synergistic activity with rifampicin (RIF) and additive activity with isoniazid (INH) and ethambutol (EMB). Additional time-kill studies showed that the compound is bacteriostatic to mycobacteria, but cytotoxic to the Chinese Hamster Ovarian (CHO) cell line. From a second generation library, two compounds showed improved anti-TB activity against M. tuberculosis H37Rv and decreased CHO cell cytotoxicity. The compounds exhibited MIC values of 2.62 µg/mL (5.6 µM) and 3.07 µg/mL (5.6 µM) respectively. The improved cytotoxicity against CHO cell line of the two compounds ranged from IC50 = 38.24 µg/mL to IC50 = 45.58 µg/mL when compared to the most active first-generation compound (IC50 = 1.82 µg/mL). The two second generation leads with selectivity indices (SI) of 14.64 and 14.85 respectively, warrant further development as anti-TB drug candidates. © 2016 IUBMB Life, 68(8):612-620, 2016.

Keywords: antimycobacterial; cytotoxicity; furanone; selective; synergy; synthetic.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antitubercular Agents / administration & dosage*
  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry
  • CHO Cells / drug effects
  • CHO Cells / microbiology
  • Cricetulus
  • Drug Synergism
  • Ethambutol / administration & dosage
  • Furans / administration & dosage*
  • Furans / chemical synthesis
  • Furans / chemistry
  • Humans
  • Isoniazid / administration & dosage
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / pathogenicity
  • Rifampin / administration & dosage
  • Tuberculosis / drug therapy*
  • Tuberculosis / microbiology


  • Antitubercular Agents
  • Furans
  • Ethambutol
  • Isoniazid
  • Rifampin