Design of a Thiosemicarbazide-Functionalized Calix[4]arene Ligand and Related Transition Metal Complexes: Synthesis, Characterization, and Biological Studies

Abstract

In this study, we synthesized a new thiosemicarbazide-functionalized calix[4]arene L and its Co2+, Ni2+, Cu2+, and Zn2+ transition metal complexes. For characterization several techniques were employed: Fourier-transform infrared (FT-IR), 1H nuclear magnetic resonance (NMR), 13C-NMR, 15N-NMR, correlation spectroscopy (COZY), nuclear Overhauser enhancement spectroscopy (NOESY), electrospray ionization (ESI)–mass spectroscopy, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and elemental analysis. To explore the capability of the thiosemicarbazide function hosted on a calix[4]arene scaffold for growth inhibition of bacteria, fungi, and cancerous tumor cells, a series of biological evaluations were performed. For L, the antimicrobial tests revealed a higher antibacterial activity against gram-positive Bacillus subtilis and a lower activity against gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), whereas the gram-positive Staphylococcus aureus shows resistance. All examined metal derivatives show an enhancement of the antibacterial activity against gram-negative E. coli bacteria, with a more significant improvement for the Ni2+ and Zn2+ complexes. MTT assays showed a considerable in vitro anticancer activity of Co2+, Ni2+, and Cu2+ complexes against Saos-2 bone cancer cell lines. The activity is ascribable to the inorganic ions rather than calixarene ligand. Hemolysis assay results demonstrated that all compounds have high blood compatibility.

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

“…Comparing these results with our recently published paper [49] reveals that the thiosemicarbazone schiff-base ligand is a stronger antimicrobial agent than its thiosemicarbazide analogue. Its antibacterial activity (MIC value) increased 8-fold and 2-fold against E. coli and P. aeruginosa, respectively, in comparison with thiosemicarbazide.…”

“…The Co derivative spectrum ( Figure S7) is in agreement with a di-cationic complex with formula LCo(II)Co(III) 2+ , formed by the loss of 3 H + from L, [C64H75N6O6S2Co2] 2+ . Analogous partial oxidation of the Co 2+ species was also observed for the compound 5 derivative [49]. The HRMS spectrum of the Ni derivative ( Figure S8) reveals the presence of multiple species, including a mixture of monomeric and dimeric complexes of a monodeprotonated ligand, with formula LNi(II) + and L2Ni(II)2 2+ , [C64H77N6O6S2Ni] + and [C128H154N12O12S4Ni2] 2+ ( Figure S9), and a di-cationic complex of L 2− with formula LNi(II)2 2 , [C64H76N6O6S2Ni2] 2+ .…”

“…Comparison of these results with those obtained from our previously published thiosemicarbazide ligand and its metal derivatives [49] indicates that the thiosemicarbazone Schiff-based ligand is a more effective anti-cancer agent against Saos-2 cancer cells versus thiosemicarbazide ligand (IC 50 < 25 µg/mL versus IC 50 > 200 µg/mL) even at lower concentrations. Considering the present Ni and Cu derivatives, it is apparent that the IC 50 values (as a criterion of anticancer activity) decreased 3.22-fold (decrease from 200 µg/ml to 62 µg/ml) and 3.95-fold (decrease from 170 µg/mL to 43 µg/mL), respectively, in comparison with their thiosemicarbazide analogues.…”

“…Literature procedures for the synthesis of p-tert-butylcalix [4]arene (1), 1,3 dinitrile-substituted p-tert-butylcalix [4]arene (2), 1,3 diamine-substituted p-tert-butylcalix [4]arene (3), and 1,3 diisocyanatesubstituted p-tert-butylcalix [4]arene (4) were followed [48,59,60]. Bisthiosemicarbazide-substituted p-tert-butylcalix [4]arene (5) was prepared as described in our recent paper [49].…”

“…The pure diffraction is due to the small crystal size (rods with typical dimensions of 0.1 × 0.05 × 0.02 mm), as well as the significant solvent disorder observed (see below). Diffraction data were indexed and integrated using the XDS package [61] while scaling was carried out with XSCALE [49]. The structure was solved using the SHELXT program [62] and structure refinement was performed with SHELXL-14 by full-matrix least-squares (FMLS) methods on F 2 [63] operating through the WinGX GUI [64].…”