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Open AccessArticle

Synthesis, Crystal Structure, and Biological Activity of a Multidentate Calix[4]arene Ligand Doubly Functionalized by 2-Hydroxybenzeledene-Thiosemicarbazone

1
Department of Inorganic Chemistry, Faculty of Chemistry, University of Tabriz, 5166616471 Tabriz, Iran
2
Centre of Excellence in Biocrystallography, Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127 Trieste, Italy
3
Drug Applied Research Center, Tabriz University of Medical Sciences, 5154853431 Tabriz, Iran
*
Authors to whom correspondence should be addressed.
Academic Editors: Mario Berberan-Santos and Paula M. Marcos
Molecules 2020, 25(2), 370; https://doi.org/10.3390/molecules25020370
Received: 11 November 2019 / Revised: 10 January 2020 / Accepted: 14 January 2020 / Published: 16 January 2020
(This article belongs to the Special Issue Calixarene Complexes: Synthesis, Properties and Applications)
The design and synthesis of a novel tert-butyl-calix[4]arene functionalized at 1, 3 positions of the lower rim with two terminal 2-hydroxybenzeledene-thiosemicarbazone moieties is reported. The new ligand with multi-dentate chelating properties was fully characterized by several techniques: ESI-Mass spectroscopy, FT-IR, 1H-NMR, and single crystal X-ray diffraction. The solid state structure confirms that the calix[4]arene macrocycle has the expected open cone conformation, with two opposite phenyl rings inclined outwards with large angles. The conformation of the two alkoxythiosemicarbazone arms produces a molecule with a C2 point group symmetry. An interesting chiral helicity is observed, with the two thiosemicarbazone groups oriented in opposite directions like a two-blade propeller. A water molecule is encapsulated in the center of the two-blade propeller through multiple H-bond coordinations. The antibacterial, antifungal, anticancer, and cytotoxic activities of the calix[4]arene-thiosemicarbazone ligand and its metal derivatives (Co2+, Ni2+, Cu2+, and Zn2+) were investigated. A considerable antibacterial activity (in particular against E. coli, MIC, and MBC = 31.25 μg/mL) was observed for the ligand and its metal derivatives. Significant antifungal activities against yeast (C. albicans) were also observed for the ligand (MIC = 31.25 μg/mL and MBC = 125 μg/mL) and for its Co2+ derivative (MIC = 62.5 μg/mL). All compounds show cytotoxicity against the tested cancerous cells. For the Saos-2 cell line, the promising anticancer activity of ligand L (IC50 < 25 μg/mL) is higher than its metal derivatives. The microscopic analysis of DAPI-stained cells shows that the treated cells change in morphology, with deformation and fragmentation of the nuclei. The hemo-compatibility study demonstrated that this class of compounds are suitable candidates for further in vivo investigations. View Full-Text
Keywords: thiosemicarbazone; calix[4]arene; metal complex; X-ray structure; antimicrobial; anticancer thiosemicarbazone; calix[4]arene; metal complex; X-ray structure; antimicrobial; anticancer
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MDPI and ACS Style

Bahojb Noruzi, E.; Shaabani, B.; Geremia, S.; Hickey, N.; Nitti, P.; Kafil, H.S. Synthesis, Crystal Structure, and Biological Activity of a Multidentate Calix[4]arene Ligand Doubly Functionalized by 2-Hydroxybenzeledene-Thiosemicarbazone. Molecules 2020, 25, 370.

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