Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents

• Published in: Journal of antibiotics Vol. 66; no. 6; pp. 319 - 325
• Main Authors: Shen, Li, M Maddox, Marcus, Adhikari, Sudip, Bruhn, David F, Kumar, Manish, Lee, Robin E, Hurdle, Julian G, Lee, Richard E, Sun, Dianqing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2013; Nature Publishing Group
• Subjects: 631/154/349; 631/61/338/22; 692/699/255/1318; Amination; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Bacterial diseases; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; Chromatography - methods; Diarylheptanoids - analogs & derivatives; Diarylheptanoids - chemistry; Diarylheptanoids - pharmacology; Drug Evaluation, Preclinical; E coli; Escherichia coli - drug effects; Hydrogenation; Isomerism; Life Sciences; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Medicinal Chemistry; Microbial Sensitivity Tests; Microbiology; Mycobacterium tuberculosis - drug effects; Organic Chemistry; original-article; Oximes - chemical synthesis; Oximes - chemistry; Small Molecule Libraries - chemistry; Structure-Activity Relationship; pterocarine; engelhardione; macrocycle; antibacterial; antitubercular; diarylheptanoid
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/ja.2013.21

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.