Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents Academic Article uri icon


  • The natural product engelhardione is an underexplored chemotype for developing novel treatments for bacterial infections; we therefore explored this natural product scaffold for chemical diversification and structure-activity relationship studies. Macrocyclic engelhardione and structural regioisomers were synthesized using a series of aldol condensations and selective hydrogenations to generate the 1,7-diarylheptan-3-one derivatives, followed by microwave-assisted intramolecular Ullmann coupling to afford a series of macrocyclic diaryl ether analogs. An extended macrocyclic chemical library was then produced by oxime formation, reductive amination and O-alkylation. Antibacterial evaluation revealed that the reductive amination derivatives 7b and 7d showed moderate activities (minimum inhibitory concentrations: 12.5-25 μg ml(-1)) against Mycobacterium tuberculosis and Gram-positive pathogens, as well as anti-Gram-negative activity against an efflux impaired Escherichia coli strain. These results provide validated leads for further optimization and development.

author list (cited authors)

  • Shen, L. i., M Maddox, M., Adhikari, S., Bruhn, D. F., Kumar, M., Lee, R. E., ... Sun, D.

citation count

  • 11

publication date

  • April 2013