title: Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates.
abstract: A series of new thiophene-based guanylhydrazones (iminoguanidines) were synthesized in high yields using a straightforward two-step procedure. The antifungal activity of compounds was evaluated against a wide range of medicaly important fungal strains including yeasts, molds, and dermatophytes in comparison to clinically used drug voriconazole. Cytotoxic properties of compounds were also determined using human lung fibroblast cell line and hemolysis assay. All guanylhydrazones showed significant activity against broad spectrum of clinically important species of Candida spp., Aspergillus fumigatus, Fusarium oxysporum, Microsporum canis and Trichophyton mentagrophytes, which was in some cases comparable or better than activity of voriconazole. More importantly, compounds 10, 11, 13, 14, 18 and 21 exhibited excellent activity against voriconazole-resistant Candida albicans CA5 with very low minimal inhibitory concentration (MIC) values <2 μg mL(-1). Derivative 14, bearing bromine on the phenyl ring, was the most effective compound with MICs ranging from 0.25 to 6.25 μg mL(-1). However, bis-guanylhydrazone 18 showed better selectivity in terms of therapeutic index values. In vivo embryotoxicity on zebrafish (Danio rerio) showed improved toxicity profile of 11, 14 and 18 in comparison to that of voriconazole. Most guanylhydrazones also inhibited C. albicans yeast to hyphal transition, essential for its biofilm formation, while 11 and 18 were able to disperse preformed Candida biofilms. All guanylhydrazones showed the equal potential to interact with genomic DNA of C. albicans in vitro, thus indicating a possible mechanism of their action, as well as possible mechanism of observed cytotoxic effects. Tested compounds did not have significant hemolytic effect and caused low liposome leakage, which excluded the cell membrane as a primary target. On the basis of computational docking experiments using both human and cytochrome P450 from Candida it was concluded that the most active guanylhydrazones had minimal structural prerequisites to interact with the cytochrome P450 14α-demethylase (CYP51). Promising guanylhydrazone derivatives also showed satisfactory pharmacokinetic profile based on molecular calculations.
authors: Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 51, 11158 Belgrade, Serbia.
authors: Vladimir
authors: V
authors: Ajdačić
authors: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia.
authors: Lidija
authors: L
authors: Senerovic
authors: Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 51, 11158 Belgrade, Serbia.
authors: Marija
authors: M
authors: Vranić
authors: National Reference Medical Mycology Laboratory, Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia.
authors: Marina
authors: M
authors: Pekmezovic
authors: National Reference Medical Mycology Laboratory, Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia.
authors: Valentina
authors: V
authors: Arsic-Arsnijevic
authors: Faculty of Medicine, Department of Chemistry, University of Niš, 18000 Niš, Serbia.
authors: Aleksandar
authors: A
authors: Veselinovic
authors: Faculty of Medicine, Department of Chemistry, University of Niš, 18000 Niš, Serbia.
authors: Jovana
authors: J
authors: Veselinovic
authors: Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 51, 11158 Belgrade, Serbia.
authors: Bogdan A
authors: BA
authors: Šolaja
authors: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia. Electronic address: jasmina.nikodinovic@gmail.com.
authors: Jasmina
authors: J
authors: Nikodinovic-Runic
authors: Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 51, 11158 Belgrade, Serbia. Electronic address: igorop@chem.bg.ac.rs.
authors: Igor M
authors: IM
authors: Opsenica
mesh_terms: D001232:Aspergillus fumigatus / Q000187:drug effects; D002175:Candida / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D005670:Fusarium / Q000187:drug effects; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008864:Microsporum / Q000187:drug effects; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D014249:Trichophyton / Q000187:drug effects; D065819:Voriconazole / Q000494:pharmacology*
chemical_list: D006146:Guanidines; D013876:Thiophenes; D065819:Voriconazole
keywords: Antifungal; Biofilm; Fungicidal; Guanlylhydrazone; Voriconazole-resistant Candida