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

• Main Authors: Ehsan Bahojb Noruzi, Behrouz Shaabani, Silvano Geremia, Neal Hickey, Patrizia Nitti, Hossein Samadi Kafil
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Molecules
• Subjects: thiosemicarbazone; calix[4]arene; metal complex; x-ray structure; antimicrobial; anticancer
• Online Access: https://www.mdpi.com/1420-3049/25/2/370

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 <i>E. coli</i>, MIC, and MBC = 31.25 &#956;g/mL) was observed for the ligand and its metal derivatives. Significant antifungal activities against yeast (<i>C. albicans</i>) were also observed for the ligand (MIC = 31.25 &#956;g/mL and MBC = 125 &#956;g/mL) and for its Co²⁺ derivative (MIC = 62.5 &#956;g/mL). All compounds show cytotoxicity against the tested cancerous cells. For the Saos-2 cell line, the promising anticancer activity of ligand L (IC₅₀ &lt; 25 &#956;g/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.