title: Synthesis and evaluation of anti-tubercular activity of new dithiocarbamate sugar derivatives.
abstract: The present study was undertaken to optimize the anti-tubercular activity of 2-acetamido-2-deoxy-β-D-glucopyranosyl N,N-dimethyldithiocarbamate (OCT313, Glc-NAc-DMDC), a lead compound previously reported by us. Structural modifications of OCT313 included the replacements of the DMDC group at C-1 by pyrrolidine dithiocarbamate (PDTC) and the acetyl group at C-2 by either propyl, butyl, benzyl or oleic acid groups. The antimycobacterial activities of these derivatives were evaluated against Mycobacterium tuberculosis (MTB). Glc-NAc-pyrrolidine dithiocarbamate (OCT313HK, Glc-NAc-PDTC) exhibited the most potent anti-tubercular activity with the minimal inhibitory concentration (MIC) of 6.25-12.5 μg/ml. The antibacterial activity of OCT313HK was highly specific to MTB and Mycobacterium bovis BCG, but not against Mycobacterium avium, Mycobacterium smegmatis, Staphylococcus aureus or Escherichia coli. Importantly, OCT313HK was also effective against MTB clinical isolates, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Interestingly, OCT313HK was exerted the primary bactericidal activity, and it was also exhibited the bacteriolytic activity at high concentrations. We next investigated whether the mycobacterial monooxygenase EthA, a common activator of thiocarbamide-containing anti-tubercular drugs, also activated OCT313HK. Contrary to our expectations, the anti-tubercular activity of dithiocarbamate sugar derivatives and dithiocarbamates were not dependent on ethA expression, in contrast to thiocarbamide-containing drugs. Overall, this study presents OCT313HK as a novel and potent compound against MTB, particularly promising to overcome drug resistance.
authors.affiliation: Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Horita
authors.forename: Takemasa
authors.initials: T
authors.lastname: Takii
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kuroishi
authors.forename: Taku
authors.initials: T
authors.lastname: Chiba
authors.forename: Kenji
authors.initials: K
authors.lastname: Ogawa
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sato
authors.forename: YooSa
authors.initials: Y
authors.lastname: Lee
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Kikuo
authors.initials: K
authors.lastname: Onozaki
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002241:Carbohydrates / Q000737:chemistry*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013863:Thioglucosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C557876:2-acetamido-2-deoxyglucopyranosyl pyrrolidine-1-carbodithioate; D000995:Antitubercular Agents; D002241:Carbohydrates; D013859:Thiocarbamates; D013863:Thioglucosides; D010088:Oxidoreductases; C480352:ethA protein, Mycobacterium tuberculosis