MenA is a promising drug target for developing novel lead molecules to combat Mycobacterium tuberculosis.
Potent inhibitors of MenA (1,4-dihydroxy-2-naphtoate prenyltrasferase) in Mycobacterium tuberculosis are identified, and are also effective in inhibiting growth of Mycobacterium tuberculosis at low concentrations. The MenA inhibitors possess common chemical structural features of (alkylamino)oalkoxyphenyl)(phenyl)methanones. Significantly, the MenA inhibitors can be synthesized in a few steps with high overall yields. The representative MenA inhibitors are highly effective in killing nonreplicating Mycobacterium tuberculosis that is evaluated by using the Wayne low oxygen model. In addition, a series of drug resistant Mycobacterium spp. are sensitive to the MenA inhibitors. The results are expected to be of significance in terms of discovering new lead compounds that can be developed into new drugs to combat unmet diseases caused by Mycobacterium tuberculosis.
Kurosu
Michio
M
Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1682, USA. michio.kurosu@colostate.edu
Crick
Dean C
DC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001577:Benzophenones / Q000494:pharmacology; D002384:Catalysis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D050296:Microbial Viability / Q000187:drug effects; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology*; D024482:Vitamin K 2 / Q000378:metabolism
D001426:Bacterial Proteins; D001577:Benzophenones; D004791:Enzyme Inhibitors; C523810:allylaminomethanone-A; D024482:Vitamin K 2; C573554:1,4-dihydroxy-2-naphthoate prenyltransferase, Mycobacterium tuberculosis; D019883:Alkyl and Aryl Transferases; D004122:Dimethylallyltranstransferase; D007538:Isoniazid; D012293:Rifampin