title: Characterization of 7-amino-4-methylcoumarin as an effective antitubercular agent: structure-activity relationships.
abstract: OBJECTIVE
  The objective of the present study was to evaluate the antitubercular activity of amino and acyl amino derivatives of coumarins when used alone and in combination with isoniazid, rifampicin, streptomycin or ethambutol, and to decipher the mode of action of the most effective agent.
  
  
  METHODS
  A series of amino and acyl amino coumarins were synthesized and screened for activity against the Mycobacterium tuberculosis H37Rv strain. These compounds were further evaluated by standard assay procedures to determine their MBCs, fractional inhibitory concentration index values and cytotoxicities. The MICs for a susceptible and a multidrug-resistant clinical isolate of M. tuberculosis were also determined. Electron and fluorescence microscopy of the test compound-treated mycobacterial samples were also carried out in an attempt to find out the target of action.
  
  
  RESULTS
  7-Amino-4-methylcoumarin (7-amino-4-methyl-2H-chromen-2-one; NA5) displayed the lowest MIC of 1 mg/L against not only H37Rv but also the susceptible as well as the multidrug-resistant clinical isolates. Certain acyl amino coumarins were also found to inhibit the aforementioned strains and isolates with MICs in the range of 1.0-3.5 mg/L. They were also found to act in synergy with isoniazid/rifampicin. Electron microscopy revealed the cell-wall-attacking characteristic of these compounds, while fluorescence microscopy indicated that mycolic acid might be the target of action.
  
  
  CONCLUSIONS
  The present study clearly demonstrated the in vitro antitubercular potential of the novel drug candidate NA5. Further studies are warranted to establish the in vivo efficacy and therapeutic potential of NA5.
authors.affiliation: Department of Biochemistry, V. P. Chest Institute, University of Delhi, Delhi 110 007, India.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Tandon
authors.forename: Prija
authors.initials: P
authors.lastname: Ponnan
authors.forename: Neha
authors.initials: N
authors.lastname: Aggarwal
authors.forename: Rakesh
authors.initials: R
authors.lastname: Pathak
authors.forename: Anil S
authors.initials: AS
authors.lastname: Baghel
authors.forename: Garima
authors.initials: G
authors.lastname: Gupta
authors.forename: Anu
authors.initials: A
authors.lastname: Arya
authors.forename: Mahendra
authors.initials: M
authors.lastname: Nath
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.forename: Hanumantharao G
authors.initials: HG
authors.lastname: Raj
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Prasad
authors.forename: Mridula
authors.initials: M
authors.lastname: Bose
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004977:Ethambutol / Q000494:pharmacology; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009171:Mycolic Acids / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D013307:Streptomycin / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D003374:Coumarins; D009171:Mycolic Acids; D004977:Ethambutol; C028743:7-amino-4-methylcoumarin; D007538:Isoniazid; D012293:Rifampin; D013307:Streptomycin