Discovery of benzothiazole amides as potent antimycobacterial agents

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Graham, James¹  Wong, Christina E.¹  Day, Joshua¹  McFaddin, Elizabeth¹  Ochsner, Urs¹  Hoang, Teresa¹  Young, Casey L.¹  Ribble, Wendy¹  DeGroote, Mary A.²  Jarvis, Thale¹  Sun, Xicheng¹ 

[1] Crestone Inc, 6075 Longbow Dr,Suite 130, Boulder, CO 80301 USA

[2] Colorado State Univ, Dept Microbiol Immunol & Pathol, Mycobacteria Res Labs, Ft Collins, CO 80523 USA

关键词: Mycobacteria;    Nontuberculous mycobacteria;    MmpL3 inhibitor;    Tuberculosis;    Benzothiazole amide;    Antibiotics;    Mycobacterium abscessus;    Mycobacterium avium;   

DOI  :  10.1016/j.bmcl.2018.08.026

来源: Elsevier

【 摘 要 】

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 mu g/mL against Mycobacterium abscessus and other rapid-grower NTM, and 1-2 mu g/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.

【 授权许可】

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