Heteroleptic silver(I), nickel(II), and copper(II) complexes of N⁴‐substituted thiosemicarbazones and ciprofloxacin: Theoretical, in vitro anti‐proliferative, and in silico molecular modeling and pharmacokinetics studies

Abstract

In this study, a series of new heteroleptic silver(I), nickel(II), and copper(II) complexes of the type [M(L1–3)(Cfx)n] (1–9), where L1–3 = N4‐substituted thiosemicarbazones (TSCs), Cfx = ciprofloxacin, M = Ag(I), Ni(II), or Cu(II), and n = 1 or 2, have been synthesized and characterized by spectral methods. The spectral data of the complexes suggest bidentate behavior of the TSC ligand, which coordinate with metal ion through thione sulphur and hydrazine nitrogen atoms, and neutral bidentate behavior of the ciprofloxacin drug that coordinates with metal ion through pyridone oxygen and one of the carboxylate oxygen atoms. The structural properties of the silver(I) complexes (1–3) were studied by density functional theory calculations, which indicate the distorted tetrahedral geometry with lower energy gap for complex 3. All the heteroleptic complexes were screened for their in vitro anti‐proliferative activity against four cancerous (lung [A549], estrogen negative [MDA‐MB‐231], estrogen positive [MCF‐7] and Henrietta's cancer cells [HeLa]), and one non‐cancerous (non‐tumorigenic human breast epithelial cell line [MCF‐10a]) cell lines by MTT reduction assay. The obtained results revealed the lower activity of silver(I) complexes and higher activity of copper(II) complexes against the tested cancer cell lines. The complexes 6 and 9 induce apoptosis in MDA‐MB‐231 cells, which was evidenced by acridine orange/ethidium bromide staining method. The molecular docking studies revealed hydrogen bonding and hydrophobic interactions between the complexes and the epidermal growth factor receptor. The in silico analysis of the complexes for Lipinski's “rule of five” and absorption, distribution, metabolism, and excretion properties predicted the drug‐likeness of the synthesized complexes.

Theoretical, in Vitro Antiproliferative, and in Silico Molecular Docking and Pharmacokinetics Studies of Heteroleptic Nickel(II) and Copper(II) Complexes of Thiosemicarbazone‐Based Ligands and Pefloxacin

“…3 T 1g (P) transitions, respectively, while the copper(II) complexes (7)(8)(9)(10)(11)(12) showed a broad absorption band at 628-655 nm, assigned to metal-centered d-d transitions. [30,31] The observed transitions support the distorted octahedral environment around nickel(II) and copper(II) ions.…”

“…All the metal complexes showed a high intensity absorption band at 272–289 nm and a medium intensity band at 318–342 nm, which are assigned to an intra‐ligand charge transfer transition (π→π*) and charge transfer from the oxygen atom of the pefloxacin moiety to the metal ion (n→π*), respectively. Further, the nickel(II) complexes ( 1 – 6 ) showed three weak absorption bands in the visible region at 728–749, 835–843 and 936–960 nm due to 3 A 2g → 3 T 2g (F), 3 A 2g → 3 T 1g (F) and 3 A 2g → 3 T 1g (P) transitions, respectively, while the copper(II) complexes ( 7 – 12 ) showed a broad absorption band at 628–655 nm, assigned to metal‐centered d–d transitions [30,31] . The observed transitions support the distorted octahedral environment around nickel(II) and copper(II) ions.…”

“…The molecular docking studies of the metal(II) complexes ( 1 – 12 ) were carried out to predict the binding modes and affinities of the complexes with H‐ras (121 p), an oncogenic protein, using the software AutoDock (ADT) version 1.5.7. All the AutoDock parameters were set in accordance with the specifications described in our previous article [30] . The DISCOVERY studio visualizer and LIG‐PLOT plus program suits were used to visualize the 3D and 2D intermolecular hydrogen bonding and hydrophobic interaction.…”

“…All the AutoDock parameters were set in accordance with the specifications described in our previous article. [30] The DISCOVERY studio visualizer and LIG-PLOT plus program suits were used to visualize the 3D and 2D intermolecular hydrogen bonding and hydrophobic interaction.…”

Ethylene-Di-Amine Modified β-Cyclodextrin Catalyzed Green Synthesis of Pyrimidones and Its In Silico Study against ESBL E. coli Receptor

“…The importance of heterocyclic frameworks is well documented in literature as depicted by its importance in various fields like material science, agrochemicals and drug discovery [10][11][12][13][14][15]. 3,4dihydropyrimidin-2(1H)-ones (DHPMs) are found to possess diverse range of pharmacological properties, including anti-tubercular, [16] antimicrobial, [17] anti-consultant, [18] anti-cancer, [19] anti-viral, [20] and anti-tubercular properties.…”