title: Synthesis and biological activity of new salicylanilide N,N-disubstituted carbamates and thiocarbamates.
abstract: The development of novel antimicrobial drugs represents a cutting edge research topic. In this study, 20 salicylanilide N,N-disubstituted carbamates and thiocarbamates were designed, synthesised and characterised by IR, (1)H NMR and (13)C NMR. The compounds were evaluated in vitro as potential antimicrobial agents against Mycobacterium tuberculosis and nontuberculous mycobacteria (Mycobacterium avium and Mycobacterium kansasii) as well as against eight bacterial and fungal strains. Additionally, we investigated the inhibitory effect of these compounds on mycobacterial isocitrate lyase and cellular toxicity. The minimum inhibitory concentrations (MICs) against mycobacteria were from 4 μM for thiocarbamates and from 16 μM for carbamates. Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, were inhibited with MICs from 0.49 μM by thiocarbamates, whilst Gram-negative bacteria and most of the fungi did not display any significant susceptibility. All (thio)carbamates mildly inhibited isocitrate lyase (up to 22%) at a concentration of 10 μM. The (thio)carbamoylation of the parent salicylanilides led to considerably decreased cytotoxicity and thus improved the selectivity indices (up to 175). These values indicate that some derivatives are attractive candidates for future research.
authors: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: martin.kratky@faf.cuni.cz.
authors: Martin
authors: M
authors: Krátký
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: marie.volkova@faf.cuni.cz.
authors: Marie
authors: M
authors: Volková
authors: Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: eva.novotna@faf.cuni.cz.
authors: Eva
authors: E
authors: Novotná
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: frantisek.trejtnar@faf.cuni.cz.
authors: František
authors: F
authors: Trejtnar
authors: Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské náměstí 7, 702 00 Ostrava, Czech Republic. Electronic address: Jirina.Stolarikova@zu.cz.
authors: Jiřina
authors: J
authors: Stolaříková
authors: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: jarmila.vinsova@faf.cuni.cz.
authors: Jarmila
authors: J
authors: Vinšová
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D005658:Fungi / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007522:Isocitrate Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects; D019909:Mycobacterium kansasii / Q000187:drug effects; D012458:Salicylanilides / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D002219:Carbamates; D012458:Salicylanilides; D013859:Thiocarbamates; D007522:Isocitrate Lyase; C034596:salicylanilide
keywords: Antimicrobial activity; Antimycobacterial activity; Cytotoxicity; Isocitrate lyase inhibition; Salicylanilide carbamate; Salicylanilide thiocarbamate