title: Salicylanilide pyrazinoates inhibit in vitro multidrug-resistant Mycobacterium tuberculosis strains, atypical mycobacteria and isocitrate lyase.
abstract: The development of antimicrobial agents represents an up-to-date topic. This study investigated in vitro antimycobacterial activity, mycobacterial isocitrate lyase inhibition and cytotoxicity of salicylanilide pyrazinoates. They may be considered being mutual prodrugs of both antimycobacterial active salicylanilides and pyrazinoic acid (POA), an active metabolite of pyrazinamide, in which these esters are likely hydrolysed without presence of pyrazinamidase/nicotinamidase. Minimum inhibitory concentrations (MICs) of the esters were within the range 0.5-8 μmol/l for Mycobacterium tuberculosis and 1-32 μmol/l for nontuberculous mycobacteria (Mycobacterium avium, Mycobacterium kansasii). All esters showed a weak inhibition (8-17%) of isocitrate lyase at the concentration of 10 μmol/l. The most active pyrazinoates showed MICs for multidrug-resistant tuberculosis strains in the range of 0.125-2 μmol/l and no cross-resistance with clinically used drugs, thus being the most in vitro efficacious salicylanilide esters with 4-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate superiority (MICs⩽0.25 μmol/l). This promising activity is likely due to an additive or synergistic effect of released POA and salicylanilides. Selectivity indexes for the most active salicylanilide pyrazinoates ranged up to 64, making some derivatives being attractive candidates for the next research; 4-bromo-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl pyrazine-2-carboxylate showed the most convenient toxicity profile.
authors: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: martin.kratky@faf.cuni.cz.
authors: Martin
authors: M
authors: Krátký
authors: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: jarmila.vinsova@faf.cuni.cz.
authors: Jarmila
authors: J
authors: Vinšová
authors: Department of Biochemical Sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: eva.novotna@faf.cuni.cz.
authors: Eva
authors: E
authors: Novotná
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
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D007522:Isocitrate Lyase / Q000037:antagonists & inhibitors; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D009170:Nontuberculous Mycobacteria / Q000187:drug effects* / Q000254:growth & development; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D012458:Salicylanilides / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D012458:Salicylanilides; D011718:Pyrazinamide; C005296:pyrazinoic acid; D007522:Isocitrate Lyase; C034596:salicylanilide
keywords: Antimycobacterial activity; In vitro activity; Isocitrate lyase inhibition; Multidrug-resistant tuberculosis; Pyrazine-2-carboxylic acid ester; Salicylanilide ester