title: Synthesis of readily available fluorophenylalanine derivatives and investigation of their biological activity.
abstract: A series of thirty novel N-acetylated fluorophenylalanine-based aromatic amides and esters was synthesized using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or phosphorus trichloride in pyridine. They were characterized by spectral methods and screened against various microbes (Mycobacterium tuberculosis, non-tuberculous mycobacteria, other bacteria, fungi), for their inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and cytotoxicity. All amino acids derivatives revealed a moderate inhibition of both cholinesterases with IC50values for AChE and BChE of 57.88-130.75µM and 8.25-289.0µM, respectively. Some derivatives were comparable or superior to rivastigmine, an established drug. Phenyl 2-acetamido-3-(4-fluorophenyl)propanoate was identified as the selective and most potent inhibitor of BChE. The esterification and amidation of parent acids led to an improved BChE inhibition. The esters are better inhibitors of BChE than the amides. The introduction of NO2and CH3groups into aniline ring and CF3moiety in phenol is translated into lower IC50values. Seven compounds showed selectivity index higher than 10 for at least one cholinesterase. Especially the esters exhibited a mild activity against Gram-positive bacteria, mycobacteria and several fungal strains with minimum inhibitory concentrations starting from 125µM. The highest susceptibility was recorded for Trichophyton mentagrophytes fungus.
authors.affiliation: Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: martin.kratky@faf.cuni.cz.
authors.forename: Martin
authors.initials: M
authors.lastname: Krátký
authors.affiliation: Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Štěpánková
authors.affiliation: Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic.
authors.forename: Katarína
authors.initials: K
authors.lastname: Vorčáková
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Navrátilová
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: František
authors.initials: F
authors.lastname: Trejtnar
authors.affiliation: Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské námĕstí 7, 702 00 Ostrava, Czech Republic.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Stolaříková
authors.affiliation: Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Vinšová
mesh_terms: D000107:Acetylation; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004593:Electrophorus; D005658:Fungi / Q000187:drug effects; D054879:Halogenation; D056945:Hep G2 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000188:drug therapy; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D002800:Cholinesterase Inhibitors; D010649:Phenylalanine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Amides; Antimicrobial activity; Cholinesterases; Cytotoxicity; Enzyme inhibition; Esters; Fluorophenylalanines; In vitro activity; Unnatural amino acids