42433-74-9Relevant academic research and scientific papers
Time-dependent diaryl ether inhibitors of InhA: Structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy
Pan, Pan,Knudson, Susan E.,Bommineni, Gopal R.,Li, Huei-Jiun,Lai, Cheng-Tsung,Liu, Nina,Garcia-Diaz, Miguel,Simmerling, Carlos,Patil, Sachindra S.,Slayden, Richard A.,Tonge, Peter J.
, p. 776 - 791 (2014/05/06)
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. No turning back: A series of diaryl ethers was designed with modifications to the B-ring. Structure-activity relationship studies shed light on the mechanism of time-dependent inhibition of InhA: during inhibitor binding, a slow step that leads to the final enzyme-inhibitor complex (EI*) is thought to correlate with closure and ordering of the substrate binding loop. In a mouse model of tuberculosis infection, two of the time-dependent InhA inhibitors synthesized decreased the antibacterial load by 0.5-0.7 log units.
Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus
Wang, Hui,Lu, Yang,Liu, Li,Kim, Sung Won,Hooker, Jacob M.,Fowler, Joanna S.,Tonge, Peter J.
, p. 66 - 73 (2015/02/19)
The pharmacokinetics (PK) and pharmacodynamics (PD) of PT119, a potent Staphylococcus aureus enoyl-ACP reductase (saFabI) inhibitor with a Ki value of 0.01 nM and a residence time of 750 min on the enzyme target, has been evaluated in mice. PT119 was found to have promising antibacterial activity in two different S. aureus infection models: it caused a 3 log reduction in the CFU's in a mouse thigh muscle infection model and increased the survival rate from 0% to 50% in a mouse systemic infection model. PT119 was then radiolabeled with carbon-11 to evaluate its biodistribution and PK in both healthy and S. aureus infected mice using positron emission tomography (PET). The biodistribution of [11C]PT119 and/or its labeled metabolites did not differ significantly between the healthy group and the infected group, and PT119 was found to distribute equally between serum and tissue during the ～1/41 h of analysis permitted by the carbon-11 half life. This approach provides important data for PK/PD modeling and is the first step in identifying radiotracers that can non-invasively image bacterial infection in vivo.
