title: Synthesis and in vitro biological evaluation of 2-(phenylcarbamoyl)phenyl 4-substituted benzoates.
abstract: Based on the previously described antimicrobial activity of salicylanilide derivatives, we designed and synthesized novel 2-(phenylcarbamoyl)phenyl 4-substituted benzoates. The most active salicylanilides were selected for esterification by various 4-substituted benzoic acids. These compounds were evaluated in vitro against Mycobacterium tuberculosis, including multidrug-resistant strains, nontuberculous mycobacteria (Mycobacterium avium and Mycobacterium kansasii), and eight bacterial and fungal strains. We also investigated the cytostatic and cytotoxic actions of the esters. The minimum inhibitory concentrations (MICs) against mycobacteria ranged from 0.125 to 8μM. Interestingly, the drug-resistant strains exhibited the highest susceptibility without any cross-resistance with established drugs. 4-Bromo-2-[4-(trifluoromethyl)phenylcarbamoyl]phenyl 4-nitrobenzoate showed the most potent inhibition with MIC values ranging from 0.25 to 2μM. Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, were inhibited by two derivatives with MIC values of at least 0.49μM, whereas Gram-negative bacteria and most of the tested fungi did not display any marked susceptibility. Benzoates exhibited no cytotoxicity at concentrations up to 50μM but most caused significant cytostasis with IC50 values lower than 10μM. Some cytotoxicity-based selectivity indexes for drug-susceptible and drug-resistant M. tuberculosis as well as Staphylococci were higher than 100. These values indicate that some of these derivatives are promising candidates for future research.
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Krátký
authors.affiliation: MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, H-1117, P.O. Box 32, 1518 Budapest 112, Hungary.
authors.forename: Szilvia
authors.initials: S
authors.lastname: Bősze
authors.affiliation: MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, H-1117, P.O. Box 32, 1518 Budapest 112, Hungary.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Baranyai
authors.affiliation: MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, H-1117, P.O. Box 32, 1518 Budapest 112, Hungary.
authors.forename: Ildikó
authors.initials: I
authors.lastname: Szabó
authors.affiliation: Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské náměstí 7, 702 00 Ostrava, Czech Republic.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Stolaříková
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Georgios
authors.initials: G
authors.lastname: Paraskevopoulos
authors.affiliation: 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.forename: Jarmila
authors.initials: J
authors.lastname: Vinšová
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005658:Fungi / Q000187:drug effects; D006801:Humans; D009161:Mycobacterium / Q000187:drug effects; D009164:Mycobacterium Infections / Q000188:drug therapy; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009181:Mycoses / Q000188:drug therapy; D014376:Tuberculosis / Q000188:drug therapy; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001565:Benzoates
keywords: Antimicrobial activity; Benzoate; Cytostasis; Cytotoxicity; Ester; In vitro activity; Multidrug-resistant tuberculosis; Mycobacterium tuberculosis; Nontuberculous mycobacteria; Salicylanilide