title: Generation and exploration of new classes of antitubercular agents: The optimization of oxazolines, oxazoles, thiazolines, thiazoles to imidazo[1,2-a]pyridines and isomeric 5,6-fused scaffolds.
abstract: Tuberculosis (TB) is a devastating disease resulting in a death every 20s. Thus, new drugs are urgently needed. Herein we report ten classes of compounds-oxazoline, oxazole, thiazoline, thiazole, pyrazole, pyridine, isoxazole, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and imidazo[1,2-c]pyrimidine-which have good (micromolar) to excellent (sub-micromolar) antitubercular potency. The 5,6-fused heteroaromatic compounds were the most potent with MIC's as low as <0.195 μM (9 and 11). Overall, the imidazo[1,2-a]pyridine class was determined to be most promising, with potency similar to isoniazid and PA-824 against replicating Mtb H(37)Rv, clinically relevant drug sensitive, multi- and extensively resistant Mtb strains as well as having good in vitro metabolic stability.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46656, USA.
authors.forename: Garrett C
authors.initials: GC
authors.lastname: Moraski
authors.forename: Lowell D
authors.initials: LD
authors.lastname: Markley
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Cho
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Chang Hwa
authors.initials: CH
authors.lastname: Hwang
authors.forename: Helena
authors.initials: H
authors.lastname: Boshoff
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Miller
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007536:Isomerism; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D007555:Isoxazoles; D010080:Oxazoles; D011725:Pyridines; D013844:Thiazoles; C001439:imidazo(1,2-a)pyridine