Abstract
The 2-aminothiazole series has anti-bacterial activity against the important global pathogen Mycobacterium tuberculosis. We explored the nature of the activity by designing and synthesizing a large number of analogs and testing these for activity against M. tuberculosis, as well as eukaryotic cells. We determined that the C-2 position of the thiazole can accommodate a range of lipophilic substitutions, while both the C-4 position and the thiazole core are sensitive to change. The series has good activity against M. tuberculosis growth with sub-micromolar minimum inhibitory concentrations being achieved. A representative analog was selective for mycobacterial species over other bacteria and was rapidly bactericidal against replicating M. tuberculosis. The mode of action does not appear to involve iron chelation. We conclude that this series has potential for further development as novel anti-tubercular agents.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antitubercular Agents / chemical synthesis*
-
Antitubercular Agents / chemistry
-
Antitubercular Agents / pharmacology*
-
Iron Chelating Agents / pharmacology
-
Microbial Sensitivity Tests
-
Mycobacterium tuberculosis / drug effects
-
Structure-Activity Relationship
-
Thiazoles / chemical synthesis*
-
Thiazoles / chemistry
-
Thiazoles / pharmacology*
-
Vero Cells
Substances
-
Antitubercular Agents
-
Iron Chelating Agents
-
Thiazoles
-
2-aminothiazole
Grants and funding
This research was funded in part by Eli Lilly and Company in support of the mission of the Lilly TB Drug Discovery Initiative and in part by grant OPP1024038 from the Bill & Melinda Gates Foundation. Funding for the Lilly TB Drug Discovery Initiative was provided by Eli Lilly and Company. The following authors are employed by Eli Lilly and Company: TM and PAH. Eli Lilly and Company provided support in the form of salaries for authors TM and PAH, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. The following authors are employed by Jubilant Chemsys Limited: SD and NK. Jubilant Chemsys Limited provided support in the form of salaries for authors SD and NK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.