title: Time-dependent diaryl ether inhibitors of InhA: structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy.
abstract: The diaryl ethers are a novel class of antituberculosis drug candidates that inhibit InhA, the enoyl-ACP reductase involved in the fatty acid biosynthesis (FASII) pathway, and have antibacterial activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. In the present work, we demonstrate that two time-dependent B-ring modified diaryl ether InhA inhibitors have antibacterial activity in a mouse model of TB infection when delivered by intraperitoneal injection. We propose that the efficacy of these compounds is related to their residence time on the enzyme, and to identify structural features that modulate drug-target residence time in this system, we have explored the inhibition of InhA by a series of B-ring modified analogues. Seven ortho-substituted compounds were found to be time-dependent inhibitors of InhA, where the slow step leading to the final enzyme-inhibitor complex (EI*) is thought to correlate with closure and ordering of the InhA substrate binding loop. A detailed mechanistic understanding of the molecular basis for residence time in this system will facilitate the development of InhA inhibitors with improved in vivo activity.
authors.affiliation: Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400 (USA).
authors.forename: Pan
authors.initials: P
authors.lastname: Pan
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.forename: Gopal R
authors.initials: GR
authors.lastname: Bommineni
authors.forename: Huei-Jiun
authors.initials: HJ
authors.lastname: Li
authors.forename: Cheng-Tsung
authors.initials: CT
authors.lastname: Lai
authors.forename: Nina
authors.initials: N
authors.lastname: Liu
authors.forename: Miguel
authors.initials: M
authors.lastname: Garcia-Diaz
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
authors.forename: Sachindra S
authors.initials: SS
authors.lastname: Patil
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007265:Inhibins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D004987:Ethers; C094377:inhibin-alpha subunit; D007265:Inhibins
keywords: InhA; diaryl ethers; enoyl-ACP reductases; fatty acid biosynthesis; inhibitors; structure-activity relationships; time-dependent inhibition