Unlocking the biological potential of transition metal complexes with Thiosemicarbazone ligands: Insights from computational studies

Abstract

In the previous study, the synthesis and characterization of 4-(3-fluorophenyl)-3-thiosemicarbazide and benzaldehyde derivatives based thiosemicarbazone ligands and their Co(II), Ni(II), Cu(II), Zn(II) complexes were carried out to evaluate their malarial and oxidant and inflammatory inhibition abilities, demonstrating that these compounds have robust efficacy for these ailments. In the present research, to find out a combating agent against breast cancer, tuberculosis, bacterial and fungal ailments, the compounds were tested through MTT, microplate alamar blue and serial dilution protocols. ADMET and DFT investigation were analyzed against highly bioactive compounds (2, 7-10) to give a new insight about compound's reactivity, stability and drug likeness properties. Furthermore, activity results shows that the ligand (2) and its complexes demonstrate greater efficacy compared to ligand (1) and its complexes. The Cu(II) (9) and Zn(II) (10) complexes were observed as highly efficient for breast cancer (MCF-7 cell line), TB (H₃₇R_v strain), bacterial and fungal ailments in comparison of standard drugs with 0.029 ± 0.001 μM IC₅₀ value for (9) in anticancer activity and 0.0034 ± 0.0017 μmol/mL MIC value for (10) in anti-tuberculosis activity. In the molecular docking investigation, the various kind of binding interactions and lowest binding affinity of (9) (against 4RJ3 (-10.0 kcal/mol), 2VCJ (-7.9 kcal/mol)) and (10) (-7.8 and -8.3 kcal/mol for 5V3Y and 3PTY protein) support their bioactivity. This research highlights the pharmaceutical importance of transition metal complexes having thiosemicarbazones, presenting a significant approach for the discovery of potent anti-infectious agent.

Keywords: ADMET; Anti-tuberculosis; Anticancer; Molecular docking; Transition metal.

Scheme 1

Synthesis of the ligands (1–2) and their transition metal complexes (3-10).

Fig. 1

Bioavailability radars of compounds (2, 7–10).

Fig. 2

LogBB and HIA % of the compounds (2, 7–10).

Fig. 3

HOMO-LUMO plots of the compounds (2, 9, 10).

Scheme 2

Structure activity relationship.

Fig. 4

Molecular docking study of the (2, 7–10) compounds for 4RJ3 protein.