Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors.
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.
am Ende
Christopher W
CW
Institute of Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
Knudson
Susan E
SE
Liu
Nina
N
Childs
James
J
Sullivan
Todd J
TJ
Boyne
Melissa
M
Xu
Hua
H
Gegina
Yelizaveta
Y
Knudson
Dennis L
DL
Johnson
Francis
F
Peloquin
Charles A
CA
Slayden
Richard A
RA
Tonge
Peter J
PJ
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
D000814:Aniline Compounds; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010647:Phenyl Ethers; D010879:Piperazines; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium