title: Inhibition of M. tuberculosis in vitro in monocytes and in mice by aminomethylene pyrazinamide analogs.
abstract: Pyrazinamide is unusual among anti-tuberculous agents in its ability to promote a durable cure and shorten the duration of therapy. Yet the basis for this effect is not well understood. A particularly effective strategy for the development of new drugs can be to synthetically manipulate the well-established structures to improve either the spectrum of activity or some pharmacological properties. Similar to previously described aminomethylene amides such as morphazinamide, it was found that novel aminomethylene amides can have in vitro activity at higher than the very acidic pH conditions where pyrazinamide is inactive as well as retaining activity against pyrazinamide-resistant M. tuberculosis. These new compounds have shown an improved anti-tuberculous activity in infected human macrophages relative to pyrazinamide. Compound 1, in combination with rifamycin, was especially effective in both infected human macrophages and in a murine model of infection. The activity of these analogs against pyrazinamide-resistant strains suggests that the development of second generation pyrazinamide analogs may be especially fruitful.
authors.affiliation: Department of Chemistry, University at Albany, Albany, NY 12203, USA.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Chung
authors.forename: Andrei
authors.initials: A
authors.lastname: Kornilov
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Brodsky
authors.forename: Michael
authors.initials: M
authors.lastname: Higgins
authors.forename: Tracy
authors.initials: T
authors.lastname: Sanchez
authors.forename: Leonid B
authors.initials: LB
authors.lastname: Heifets
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cynamon
authors.forename: John
authors.initials: J
authors.lastname: Welch
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D009000:Monocytes / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide