title: Synthesis and Evaluation of the 2-Aminothiazoles as Anti-Tubercular Agents.
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.
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Kesicki
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Mai A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Ovechkina
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Julie V
authors.initials: JV
authors.lastname: Early
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Torey
authors.initials: T
authors.lastname: Alling
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Bowman
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Edison S
authors.initials: ES
authors.lastname: Zuniga
authors.affiliation: Jubilant Chemsys Limited, B-34, Sector 58, Noida, India.
authors.forename: Suryakanta
authors.initials: S
authors.lastname: Dalai
authors.affiliation: Jubilant Chemsys Limited, B-34, Sector 58, Noida, India.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Thierry
authors.initials: T
authors.lastname: Masquelin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Hipskind
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Joshua O
authors.initials: JO
authors.lastname: Odingo
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, United States of America.
authors.forename: Tanya
authors.initials: T
authors.lastname: Parish
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D007502:Iron Chelating Agents; D013844:Thiazoles; C004483:2-aminothiazole