title: Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors.
abstract: Previous structure-based design studies resulted in the discovery of alkyl substituted diphenyl ether inhibitors of InhA, the enoyl reductase from Mycobacterium tuberculosis. Compounds such as 5-hexyl-2-phenoxyphenol 19 are nM inhibitors of InhA and inhibit the growth of both sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis with MIC(90) values of 1-2 microg/mL. However, despite their promising in vitro activity, these compounds have ClogP values of over 5. In efforts to reduce the lipophilicity of the compounds, and potentially enhance compound bioavailability, a series of B ring analogues of 19 were synthesized that contained either heterocylic nitrogen rings or phenyl rings having amino, nitro, amide, or piperazine functionalities. Compounds 3c, 3e, and 14a show comparable MIC(90) values to that of 19, but have improved ClogP values.
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: am Ende
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.forename: Nina
authors.initials: N
authors.lastname: Liu
authors.forename: James
authors.initials: J
authors.lastname: Childs
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Sullivan
authors.forename: Melissa
authors.initials: M
authors.lastname: Boyne
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.forename: Yelizaveta
authors.initials: Y
authors.lastname: Gegina
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Knudson
authors.forename: Francis
authors.initials: F
authors.lastname: Johnson
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001682:Biological Availability; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010647:Phenyl Ethers / Q000138:chemical synthesis / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010647:Phenyl Ethers; D010879:Piperazines; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium