Discovery of benzothiazole amides as potent antimycobacterial agents

Bioorganic & Medicinal Chemistry Letters
James GrahamXicheng Sun

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.

References

Dec 4, 2004·The Journal of Allergy and Clinical Immunology·Tim NiehuesVolker Wahn
May 18, 2006·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Mary A De Groote, Gwen Huitt
Jun 9, 2006·Trends in Microbiology·Liem Nguyen, Charles J Thompson
May 15, 2007·Current Opinion in Infectious Diseases·David E Griffith
May 27, 2009·Respiratory Medicine·Guillermo J BallarinoD Rebecca Prevots
Aug 28, 2009·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·C-K TanP-R Hsueh
Jan 16, 2010·Revista do Colégio Brasileiro de Cirurgiões·Nádia Suely de Oliveira LorenaMarcos Bettini Pitombo
Jan 21, 2010·Current Opinion in Infectious Diseases·David E Griffith
Jul 24, 2010·The Pediatric Infectious Disease Journal·Yael Shachor-MeyouhasImad Kassis
Sep 8, 2010·The European Respiratory Journal·A Leber, T K Marras
Dec 18, 2010·Scandinavian Journal of Infectious Diseases·Hannele KotilainenAsko Järvinen
Jan 17, 2012·American Journal of Respiratory and Critical Care Medicine·Moira L AitkenRichard J Wallace
Apr 24, 2012·Annals of the Rheumatic Diseases·K L WinthropL J Herrinton
Mar 6, 2013·Seminars in Respiratory and Critical Care Medicine·Brian A Kendall, Kevin L Winthrop
Mar 6, 2013·Seminars in Respiratory and Critical Care Medicine·Janice M Leung, Kenneth N Olivier
Mar 16, 2016·International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases·Jason E StoutWing Wai Yew
Nov 23, 2016·International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases·G J FoxJ T Denholm

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Citations

Jul 25, 2019·Antimicrobial Agents and Chemotherapy·Małgorzata Korycka-MachałaJarosław Dziadek
Oct 9, 2018·Frontiers in Microbiology·Mary A De GrooteUrs A Ochsner
Sep 2, 2020·International Journal of Molecular Sciences·Jigar P SethiyaElton Jeffrey North
Aug 28, 2021·International Journal of Molecular Sciences·Giulia DegiacomiMaria Rosalia Pasca

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