Time‐Dependent Diaryl Ether Inhibitors of InhA: Structure–Activity Relationship Studies of Enzyme Inhibition,Antibacterial Activity,and in vivo Efficacy |
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Authors: | Dr. Pan Pan Dr. Susan E. Knudson Dr. Gopal R. Bommineni Dr. Huei‐Jiun Li Cheng‐Tsung Lai Dr. Nina Liu Prof. Miguel Garcia‐Diaz Prof. Carlos Simmerling Dr. Sachindra S. Patil Prof. Richard A. Slayden Prof. Peter J. Tonge |
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Affiliation: | 1. Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794‐3400 (USA);2. Department of Microbiology, Immunology & Pathology, Colorado State University, 1619 Campus Delivery, Fort Collins, CO 80523‐2025 (USA);3. Biochemistry & Structural Biology, Stony Brook University, Stony Brook, NY 11794‐3400 (USA);4. Pharmacological Sciences Graduate Program, Stony Brook University, Stony Brook, NY 11794‐3400 (USA);5. Kanashi Biotech Pvt Ltd, A‐27 H Block MIDC, Pimpri, Pune 411018 (India) |
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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. |
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Keywords: | diaryl ethers enoyl‐ACP reductases fatty acid biosynthesis InhA inhibitors structure– activity relationships time‐dependent inhibition |
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