Discovery of Selective Menaquinone Biosynthesis Inhibitors against Mycobacterium tuberculosis

• Published in: Journal of medicinal chemistry Vol. 55; no. 8; pp. 3739 - 3755
• Main Authors: Debnath, Joy, Siricilla, Shajila, Wan, Bajoie, Crick, Dean C, Lenaerts, Anne J, Franzblau, Scott G, Kurosu, Michio
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.04.2012; Amer Chemical Soc
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Anaerobiosis; Antitubercular Agents - chemical synthesis; Antitubercular Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Chemistry, Medicinal; Electron Transport - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Escherichia coli - drug effects; Hydroxylamines - pharmacology; Life Sciences & Biomedicine; Mycobacterium tuberculosis - drug effects; Pharmacology & Pharmacy; Quinolones - pharmacology; Science & Technology; Stereoisomerism; Vitamin K 2 - analogs & derivatives; Vitamin K 2 - chemical synthesis; SYSTEM; RECOVERY; CELLS; IN-VITRO; ELECTRON; MECHANISM; ROLES; ESCHERICHIA-COLI; GROWTH; METRONIDAZOLE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201608g

Aurachin RE (1) is a strong antibiotic that was recently found to possess 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) and bacterial electron transport inhibitory activities. Aurachin RE is the only molecule in a series of aurachin natural products that has the chiral center in the alkyl side chain at C9′-position. To identify selective MenA inhibitors against Mycobacterium tuberculosis, a series of chiral molecules were designed based on the structures of previously identified MenA inhibitors and 1. The synthesized molecules were evaluated in in vitro assays, including MenA enzyme and bacterial growth inhibitory assays. We could identify novel MenA inhibitors that showed significant increase in potency of killing nonreplicating M. tuberculosis in the low oxygen recovery assay (LORA) without inhibiting other Gram-positive bacterial growth even at high concentrations. The MenA inhibitors reported here are useful new pharmacophores for the development of selective antimycobacterial agents with strong activity against nonreplicating M. tuberculosis.