Synthesis of tetrazole derivatives bearing pyrrolidine scaffold and evaluation of their antifungal activity against Candida albicans

Edyta Łukowska-Chojnacka , Anna Kowalkowska , Małgorzata Gizińska , Mirosława Koronkiewicz , Monika Staniszewska

Abstract

The increase of opportunistic fungal infections raises the need for design and synthesis of new antifungal agents. Taking into account that tetrazole derivatives exhibit antifungal activity, and some of them are in the phase of clinical trials, new tetrazole derivatives bearing pyrrolidine moiety were synthesized in order to present their action mode against C. albicans. The target compounds were obtained by N-alkylation of various 2-arylpyrrolidines with several 1-(3-chloropropyl)-5-aryl-2H-tetrazoles. Regardless of the substituents at tetrazole or pyrrolidine rings reactions took place in 48 h and with satisfactory yields ranging from 53 to 70%. We performed screen of the synthesized compounds to identify these nontoxic inhibiting the C. albicans planktonic and sessile cells, and conducted a series of follow up studies to examine the in vitro and in vivo activity of the most potent antifungals. The leading antifungal inhibitor: 2-{3-[2-(3-methylphenyl)pyrrolidin-1-yl]propyl}-5-phenyl-2H-tetrazole (3aC) and the randomly selected ones: 5-phenyl-2-[3-(2-phenylpyrrolidin-1-yl)propyl]-2H-tetrazole (3aA), 5-(4-chlorophenyl)-2-{3-[2-(4-fluorophenyl)pyrrolidin-1-yl]propyl}-2H-tetrazole (3cD), and 5-(4-chlorophenyl)-2-{3-[2-(4-chlorophenyl)pyrrolidin-1-yl]propyl}-2H-tetrazole (3cE) showed little to no toxicity against the Vero cell line and Galleria mellonella. 3aC and 3aD, the most active against biofilm in vitro, demonstrated in vivo activity in the invertebrate model of disseminated candidiasis. Flow cytometry analysis showed that necrotic cell death was generated under 3aC due to its interactions with the fungal membrane; this confirmed by the mitochondrial damage (XTT assay) and reduced adhesion to the TR-146 cell line at 46.05 M. Flow cytometry was used to directly measure the redox state of the treated cells with the fluorescent DCFH probe. Pro-necrotic tetrazole derivatives (3aA, 3aC, 3cD) are unable to induce ROS production in the C. albicans cells. Moreover, CLSM analyses revealed that the tetrazole derivatives (principally 3aC, 3aD, and 3aE) inhibit C. albicans’ ability to neutralize macrophages; a more effective phagosomes organization was observed. 3aC’s and 3aD’s activity reflected in an attenuation of virulence in disseminated candidiasis in vivo.
Author Edyta Łukowska-Chojnacka (FC / CDSB)
Edyta Łukowska-Chojnacka,,
- Chair of Drug and Cosmetics Biotechnology
, Anna Kowalkowska (FC / CDSB)
Anna Kowalkowska,,
- Chair of Drug and Cosmetics Biotechnology
, Małgorzata Gizińska
Małgorzata Gizińska,,
-
, Mirosława Koronkiewicz
Mirosława Koronkiewicz,,
-
, Monika Staniszewska
Monika Staniszewska,,
-
Journal seriesEuropean Journal of Medicinal Chemistry, ISSN 0223-5234, (A 40 pkt)
Issue year2019
Vol164
Pages106-120
Publication size in sheets0.7
Keywords in English tetrazole, pyrrolidine, azole, antifungal activity, Candida albicans
ASJC Classification1605 Organic Chemistry; 3002 Drug Discovery; 3004 Pharmacology; 2700 General Medicine
DOIDOI:10.1016/j.ejmech.2018.12.044
URL https://www.sciencedirect.com/science/article/pii/S022352341831081X?via%3Dihub
Languageen angielski
File
wdpb_publikacje_pliki_plik_publikacja_3632_org.pdf 2.43 MB
Score (nominal)40
ScoreMinisterial score = 40.0, 18-07-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.562; WoS Impact Factor: 2017 = 4.816 (2) - 2017=4.527 (5)
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