Molecular docking, PASS analysis, bioactivity score prediction, synthesis, characterization and biological activity evaluation of a functionalized 2-butanone thiosemicarbazone ligand and its complexes

Abstract

2-Butanone thiosemicarbazone ligand was prepared by condensation reaction between thiosemicarbazide and butanone. The ligand was characterized by ¹H NMR, ¹³C NMR, FT-IR, mass spectrometry and UV spectroscopic studies. Docking studies were performed to study inhibitory action against topoisomerase II (Topo II) and ribonucleoside diphosphate reductase (RR) enzymes. Inhibition constants (K_i ) of the ligand were 437.87 and 327.4 μM for the two enzymes, respectively. The ligand was tested for its potential anticancer activity against two cancer cell lines MDA-MB-231 and A549 using MTT assay and was found to exhibit good activity at higher doses with an IC₅₀ = 80 μM against human breast cancer cell line MDA-MB-231. On the other hand, no significant activity was obtained against the lung carcinoma cell line A549. Antibacterial activity of the ligand was tested against Staphylococcus aureus and E. coli using the disc diffusion method. Ligand did not exhibit any significant antibacterial activity. Four complexes of Co(III), Fe(II), Cu(II), and Zn(II) were prepared with the ligand and characterized by various spectroscopic studies. Low molar conductance values were obtained for all complexes displaying non-electrolyte nature except in Co(III) complex. As expected, complexation with metal ions significantly increased the cytotoxicity of the ligand against the tested cell lines viz. IC₅₀ values of <20 μM for Co, Fe, and Zn complexes and approx. 80 μM against MDA cells versus IC₅₀ value of <20 μM for Co and Cu complexes and that of 30 and 50 μM for Fe and Zn complexes, respectively, against A549 cells. The Cu complex was found to be active against E. coli and S. aureus with MIC values in the range of 6-10 mg/mL. Other than Cu, only Co complex was found to possess antibacterial activity with MIC values of 5-10 mg/mL when tested against S. aureus. Bioactivity score and Prediction of Activity Spectra for Substances (PASS) analysis also depicted the drug-like nature of ligand and complexes.

Keywords: Antibacterial; Anticancer; Docking; PASS; Ribonucleotide reductase; Thiosemicarbazone; Topoisomerase II.

Fig. 1

Docking pose of ligand (a), its Fe complex (b), and Zn complex (c) in the active site of Topo II

Fig. 2

Docking pose of ligand (a), its Fe complex (b), and Zn complex (c) in the active site of RR

Fig. 3

Synthesis scheme

Fig. 4

a–e Dose-dependent effect of ligand (a), its Co (b), Fe (c), Cu (d), and Zn (e) complexes on viability of MDA cells in vitro using MTT assay. Final concentration of DMSO in each well did not exceed 0.5% (v/v). Results were expressed as mean ± SD of experiments done in triplicates.

Fig. 5

a–e Dose-dependent effect of ligand (a), its Co (b), Fe (c), Cu (d), and Zn (e) complexes on viability of A549 cells in vitro using MTT assay. Final concentration of DMSO in each well did not exceed 0.5% (v/v). Results were expressed as mean ± SD of experiments done in triplicates.

Fig. 6

Antibacterial activity of ligand (a), its Co (b), Fe (b), Cu (c), and Zn (d) complexes against S. aureus using disc diffusion method

Fig. 7

Antibacterial activity of ligand (a), its Co (b), Fe (b), Cu (c), and Zn (d) complexes against E. coli using disc diffusion method