Discovery of benzothiazole amides as potent antimycobacterial agents |
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Authors: | James Graham Christina E. Wong Joshua Day Elizabeth McFaddin Urs Ochsner Teresa Hoang Casey L. Young Wendy Ribble Mary A. DeGroote Thale Jarvis Xicheng Sun |
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Affiliation: | 1. Crestone, Inc, 6075 Longbow Dr. Suite 130, Boulder, CO 80301, USA;2. Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA |
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Abstract: | From a high throughput screening of commercially available libraries against nontuberculous mycobacteria and Mycobacterium tuberculosis, numerous hits were identified with moderate activity. Extensive medicinal chemistry optimization has led to a series of potent benzothiazole amide antimycobacterial agents. Replacement of the adamantyl group with cyclohexyl derivatives and further development of this series resulted in an advanced lead compound, CRS400393, which demonstrated excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12?μg/mL against Mycobacterium abscessus and other rapid-grower NTM, and 1–2?μg/mL against Mycobacterium avium complex. The preliminary mechanism of action studies suggested these agents may target MmpL3, a mycobacterial mycolic acid transporter. The series has demonstrated in vivo efficacy in a proof of concept mouse model of M. abscessus infection. |
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Keywords: | NTM SAR structure activity relationship MIC minimum inhibitory concentration RHS right hand side LHS left hand side ADME absorption, distribution, metabolism, and excretion PK pharmacokinetics CYP cytochrome P450 RGM rapid growing mycobacteria SGM slowly growing mycobacteria Mycobacteria Nontuberculous mycobacteria MmpL3 inhibitor Tuberculosis Benzothiazole amide Antibiotics Corresponding author. |
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