title: Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Maddox
authors.forename: Sudip
authors.initials: S
authors.lastname: Adhikari
authors.forename: David F
authors.initials: DF
authors.lastname: Bruhn
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.forename: Robin E
authors.initials: RE
authors.lastname: Lee
authors.forename: Julian G
authors.initials: JG
authors.lastname: Hurdle
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
authors.forename: Dianqing
authors.initials: D
authors.lastname: Sun
mesh_terms: D000586:Amination; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002845:Chromatography / Q000379:methods; D036381:Diarylheptanoids / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000187:drug effects; D006865:Hydrogenation; D007536:Isomerism; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D036381:Diarylheptanoids; D047028:Macrocyclic Compounds; D010091:Oximes; D054852:Small Molecule Libraries
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