title: Synthesis and evaluation of new 2-aminothiophenes against Mycobacterium tuberculosis.
abstract: Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37RV (MIC = 0.23 μM) and showed an impressive potency (MIC = 0.20-0.44 μM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Toledo, 2801 W. Bancroft Street, Toledo, OH, USA 43606.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Thanna
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523.
authors.forename: Anna
authors.initials: A
authors.lastname: Grzegorzewicz
authors.affiliation: Department of Chemistry and Biochemistry, The University of Toledo, 2801 W. Bancroft Street, Toledo, OH, USA 43606.
authors.forename: Sunayana
authors.initials: S
authors.lastname: Kapil
authors.affiliation: Department of Chemistry and Biochemistry, The University of Toledo, 2801 W. Bancroft Street, Toledo, OH, USA 43606.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Goins
authors.affiliation: Department of Chemistry and Biochemistry, The University of Toledo, 2801 W. Bancroft Street, Toledo, OH, USA 43606.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Ronning
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523.
authors.forename: Mary
authors.initials: M
authors.lastname: Jackson
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
authors.affiliation: Department of Chemistry and Biochemistry, The University of Toledo, 2801 W. Bancroft Street, Toledo, OH, USA 43606.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Sucheck
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D009171:Mycolic Acids / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D009171:Mycolic Acids; D013876:Thiophenes