title: New nitrofurans amenable by isocyanide multicomponent chemistry are active against multidrug-resistant and poly-resistant Mycobacterium tuberculosis.
abstract: A set of structurally diverse N-amino δ-lactams decorated with a 5-nitro-2-furyl moiety was synthesized using isocyanide-based multicomponent chemistry and evaluated for antibacterial activity. Three compounds displayed a selective and potent (MIC 22-33μM) inhibition of M. tuberculosis H37Rv strain growth, while other Gram-positive (MRSA and E. faecium) or Gram-negative (E. coli, P. aeruginosa, A. baumannii, K. pneumoniae) pathogens were not affected. The compounds also displayed moderate-low cytotoxicity, as demonstrated in cell line viability assays. Several multidrug- and poly-resistant patient-derived M. tuberculosis strains were found to be susceptible to treatment with these compounds. The three most potent compounds share a significant structural similarity which provides a basis for further scaffold-hopping analog design.
authors.affiliation: Institutes of Chemistry and Translational Biomedicine, Saint Petersburg State University, Saint Petersburg 199034, Russian Federation. Electronic address: m.krasavin@spbu.ru.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Krasavin
authors.affiliation: Chemical Diversity Research Institute, Khimki, Moscow Region 141400, Russian Federation.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Parchinsky
authors.affiliation: Institutes of Chemistry and Translational Biomedicine, Saint Petersburg State University, Saint Petersburg 199034, Russian Federation.
authors.forename: Grigory
authors.initials: G
authors.lastname: Kantin
authors.affiliation: Saint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, Saint Petersburg 191036, Russian Federation.
authors.forename: Olga
authors.initials: O
authors.lastname: Manicheva
authors.affiliation: Saint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, Saint Petersburg 191036, Russian Federation.
authors.forename: Marine
authors.initials: M
authors.lastname: Dogonadze
authors.affiliation: Saint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, Saint Petersburg 191036, Russian Federation.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Vinogradova
authors.affiliation: Helmholtz Centre for Infection Research, Inhoffenstraβe 7, 38124 Braunschweig, Germany.
authors.forename: Bianka
authors.initials: B
authors.lastname: Karge
authors.affiliation: Helmholtz Centre for Infection Research, Inhoffenstraβe 7, 38124 Braunschweig, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Brönstrup
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D003486:Cyanides / Q000737:chemistry*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009581:Nitrofurans / Q000737:chemistry / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D000995:Antitubercular Agents; D003486:Cyanides; D009581:Nitrofurans
keywords: Antitubercular; Drug resistance; Multicomponent chemistry; N-amino lactams; Nitrofurans; Patient-derived strains