Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates
Authors
Ajdačić, VladimirŠenerović, Lidija
Vranić, Marija
Pekmezović, Marina
Arsić-Arsnijević, Valentina
Veselinović, Aleksandar
Veselinović, Jovana
Šolaja, Bogdan A.
Nikodinović-Runić, Jasmina
Opsenica, Igor
Article (Accepted Version)
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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 lt 2 mu g mL(-1). Derivative 14, bearing bromine on ...the phenyl ring, was the most effective compound with MICs ranging from 0.25 to 6.25 g 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 14a-demethylase (CYP51). Promising guanylhydrazone derivatives also showed satisfactory pharmacokinetic profile based on molecular calculations. (C) 2016 Elsevier Ltd. All rights reserved.
Keywords:
Guanlylhydrazone / Antifungal / Fungicidal / Voriconazole-resistant Candida / BiofilmSource:
Bioorganic and Medicinal Chemistry, 2016, 24, 6, 1277-1291Publisher:
- Pergamon-Elsevier Science Ltd, Oxford
Funding / projects:
- The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-MESTD-Basic Research (BR or ON)-172008)
- Microbial diversity study and characterization of beneficial environmental microorganisms (RS-MESTD-Basic Research (BR or ON)-173048)
- Serbian Academy of Sciences and Arts
- European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
Note:
- This is peer-reviewed version of the following article: Ajdačić, V.; Senerovic, L.; Vranić, M.; Pekmezovic, M.; Arsic-Arsnijevic, V.; Veselinovic, A.; Veselinovic, J.; Šolaja, B. A.; Nikodinovic-Runic, J.; Opsenica, I. M. Synthesis and Evaluation of Thiophene-Based Guanylhydrazones (Iminoguanidines) Efficient against Panel of Voriconazole-Resistant Fungal Isolates. Bioorganic and Medicinal Chemistry 2016, 24 (6), 1277–1291. https://doi.org/10.1016/j.bmc.2016.01.058
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3628
DOI: 10.1016/j.bmc.2016.01.058
ISSN: 0968-0896
PubMed: 26867487
WoS: 000370822700013
Scopus: 2-s2.0-84958907899
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Institution/Community
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Ajdačić, Vladimir AU - Šenerović, Lidija AU - Vranić, Marija AU - Pekmezović, Marina AU - Arsić-Arsnijević, Valentina AU - Veselinović, Aleksandar AU - Veselinović, Jovana AU - Šolaja, Bogdan A. AU - Nikodinović-Runić, Jasmina AU - Opsenica, Igor PY - 2016 UR - https://cherry.chem.bg.ac.rs/handle/123456789/3627 AB - 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 lt 2 mu g mL(-1). Derivative 14, bearing bromine on the phenyl ring, was the most effective compound with MICs ranging from 0.25 to 6.25 g 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 14a-demethylase (CYP51). Promising guanylhydrazone derivatives also showed satisfactory pharmacokinetic profile based on molecular calculations. (C) 2016 Elsevier Ltd. All rights reserved. PB - Pergamon-Elsevier Science Ltd, Oxford T2 - Bioorganic and Medicinal Chemistry T1 - Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates VL - 24 IS - 6 SP - 1277 EP - 1291 DO - 10.1016/j.bmc.2016.01.058 ER -
@article{ author = "Ajdačić, Vladimir and Šenerović, Lidija and Vranić, Marija and Pekmezović, Marina and Arsić-Arsnijević, Valentina and Veselinović, Aleksandar and Veselinović, Jovana and Šolaja, Bogdan A. and Nikodinović-Runić, Jasmina and Opsenica, Igor", year = "2016", 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 lt 2 mu g mL(-1). Derivative 14, bearing bromine on the phenyl ring, was the most effective compound with MICs ranging from 0.25 to 6.25 g 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 14a-demethylase (CYP51). Promising guanylhydrazone derivatives also showed satisfactory pharmacokinetic profile based on molecular calculations. (C) 2016 Elsevier Ltd. All rights reserved.", publisher = "Pergamon-Elsevier Science Ltd, Oxford", journal = "Bioorganic and Medicinal Chemistry", title = "Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates", volume = "24", number = "6", pages = "1277-1291", doi = "10.1016/j.bmc.2016.01.058" }
Ajdačić, V., Šenerović, L., Vranić, M., Pekmezović, M., Arsić-Arsnijević, V., Veselinović, A., Veselinović, J., Šolaja, B. A., Nikodinović-Runić, J.,& Opsenica, I.. (2016). Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates. in Bioorganic and Medicinal Chemistry Pergamon-Elsevier Science Ltd, Oxford., 24(6), 1277-1291. https://doi.org/10.1016/j.bmc.2016.01.058
Ajdačić V, Šenerović L, Vranić M, Pekmezović M, Arsić-Arsnijević V, Veselinović A, Veselinović J, Šolaja BA, Nikodinović-Runić J, Opsenica I. Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates. in Bioorganic and Medicinal Chemistry. 2016;24(6):1277-1291. doi:10.1016/j.bmc.2016.01.058 .
Ajdačić, Vladimir, Šenerović, Lidija, Vranić, Marija, Pekmezović, Marina, Arsić-Arsnijević, Valentina, Veselinović, Aleksandar, Veselinović, Jovana, Šolaja, Bogdan A., Nikodinović-Runić, Jasmina, Opsenica, Igor, "Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates" in Bioorganic and Medicinal Chemistry, 24, no. 6 (2016):1277-1291, https://doi.org/10.1016/j.bmc.2016.01.058 . .