Characterization of 7-amino-4-methylcoumarin as an effective antitubercular agent: structure-activity relationships

• Published in: Journal of antimicrobial chemotherapy Vol. 66; no. 11; pp. 2543 - 2555
• Main Authors: Tandon, Rashmi, Ponnan, Prija, Aggarwal, Neha, Pathak, Rakesh, Baghel, Anil S., Gupta, Garima, Arya, Anu, Nath, Mahendra, Parmar, Virinder S., Raj, Hanumantharao G., Prasad, Ashok K., Bose, Mridula
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2011; Oxford Publishing Limited (England)
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - pharmacology; Biological and medical sciences; Cell Wall - drug effects; Chemical compounds; Coumarins - chemistry; Coumarins - pharmacology; Cytotoxicity; Drug resistance; Drug Resistance, Multiple, Bacterial; Drug Synergism; Ethambutol - pharmacology; Gram-positive bacteria; Isoniazid - pharmacology; Medical sciences; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycolic Acids - metabolism; Pharmacology. Drug treatments; Prescription drugs; Rifampin - pharmacology; Streptomycin - pharmacology; Structure-Activity Relationship; cell-wall attacking; synergy; amino coumarins; multidrug resistant; Coumarine derivatives; Coumarin; Cell wall; Characterization; Structure activity relation; Efficiency; Multiple resistance; Antituberculous agent; Antibacterial agent
• DOI: 10.1093/jac/dkr355
• ISSN: 0305-7453

Objectives 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.