title: Synthesis of novel tetrazole derivatives and evaluation of their antifungal activity.
abstract: With the appearance of the antifungal resistance, novel antifungal agents need to be identified. In this context new 2,5-disubstituted tetrazole derivatives containing benzothiazole, benzoxazole or phenylsulfonyl moiety were synthesized by N-alkylation of aryltetrazole with 2-[(3-chloropropyl)sulfanyl]-1,3-benzothiazole or 2-[(3-chloropropyl)sulfanyl]-1,3-benzoxazole and Michael-type addition of aryltetrazole to phenyl vinyl sulfone. The chemical structures of the synthesized compounds were confirmed by means of1H NMR,13C NMR, IR and HRMS spectral data. The compounds were tested against the moulds: Fusarium sambucinum, Fusarium oxysporum, Colletotrichum coccodes, Aspergillus niger, and the yeast Candida albicans. The results showed that among the moulds only C. coccodes was significantly sensitive to all the structures examined. All the tetrazole derivatives acted at the same level against C. albicans and demonstrated a high cell growth inhibition (97-99%) at the concentrations ranging from 16 to 0.0313μg/mL. The mode of action of 2-({3-[5-(4-chlorophenyl)-2H-tetrazol-2-yl]propyl}sulfanyl)-1,3-benzoxazole (5c) and 2-({3-[5-(2-chlorophenyl)-2H-tetrazol-2-yl]propyl}sulfanyl)-1,3-benzoxazole (5d) was established by verifying fungal growth in the presence of osmotic protector-sorbitol. The effect of compound 5c or 5d combined with Fluconazole was determined using the checkerboard method. The calculated fractional inhibitory concentration index (FIC) indicated antagonism (FIC >1). Additionally, survival experiments with lepidopteran Galleria mellonella treated with compounds 5c and 5d were performed and demonstrated the lack of toxicity of these compounds.
authors.affiliation: Faculty of Chemistry, Institute of Biotechnology, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland. Electronic address: elukowska@ch.pw.edu.pl.
authors.forename: Edyta
authors.initials: E
authors.lastname: Łukowska-Chojnacka
authors.affiliation: Faculty of Chemistry, Institute of Biotechnology, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Mierzejewska
authors.affiliation: Faculty of Chemistry, Institute of Biotechnology, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Milner-Krawczyk
authors.affiliation: Independent Laboratory of Streptomyces and Fungi Imperfecti, National Institute of Public Health-National Institute of Hygiene, Chocimska St. 24, 00-791 Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Bondaryk
authors.affiliation: Independent Laboratory of Streptomyces and Fungi Imperfecti, National Institute of Public Health-National Institute of Hygiene, Chocimska St. 24, 00-791 Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Staniszewska
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005658:Fungi / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D013777:Tetrazoles; C045574:1H-tetrazole
keywords: Antifungal activity; Azole; Benzothiazole; Benzoxazole; Tetrazole