Investigating the Biological Potency of Nitazoxanide-Based Cu(II), Ni(II) and Zn(II) Complexes Synthesis, Characterization and Anti-COVID-19, Antioxidant, Antibacterial and Anticancer Activities.

In this work, the biological potency of nitazoxanide (NTZ) was enhanced through coordination with transition metal ions Cu(II), Ni(II), and Zn(II). Initially, complexes with a ligand-metal stoichiometry of 2:1 were successfully synthesized and characterized by spectroscopic techniques and thermogravimetric methods. Measurement of the infrared spectrum revealed the bidentate nature of the ligand and excluded the possibility of the metal ion-amide group interaction. Nuclear magnetic resonance spectra showed a reduction in the NH- intensity signal and integration, indicating the possibility of enolization and the formation of keto-enol tautomers. To interpret these results, density functional theory was utilized under B3LYP/6-311G** for the free ligand and B3LYP/LANL2DZ for the metal complexes. We used UV-Vis and fluorescence spectroscopy to understand the biological properties of the complexes. This showed stronger interactions of NTZ-Cu(II) and NTZ-Ni(II) with DNA molecules than the NTZ-Zn(II) compound, with a binding constant (Kb) for the copper complex of 7.00 × 105 M-1. Both Cu(II)- and Ni(II)-NTZ had functional binding to the SARS-CoV-2 (6LU7) protease. Moreover, all metal complexes showed better antioxidation properties than the free ligand, with NTZ-Ni(II) having the best IC50 value of 53.45 µg/mL. NTZ-Ni(II) was an effective antibacterial, with a mean inhibitory concentration of 6 µM, which is close to that of ampicillin (a reference drug). The metal complexes had moderated anticancer potencies, with NTZ-Cu(II) having IC50 values of 24.5 and 21.5 against human breast cancer cells (MCF-7) and cancerous cervical tumor cells (HeLa), respectively. All obtained complexes exhibited high selectivity. Finally, the metal ions showed a practical role in improving the biological effectiveness of NTZ molecules.

Biological efficacy of novel metal complexes of Nitazoxanide: Synthesis, characterization, anti-COVID-19, antioxidant, antibacterial and anticancer activity studies.

It has been repeatedly reported that nitazoxanide (NTZ) exhibits a wide range of antiviral activities against various viral infections and has shown antimicrobial properties against anaerobic bacteria, helminths and protozoa. To improve these properties, three novel metal complexes were synthesized. The bidentate characteristic of the NTZ ligand was characterized by different spectroscopic techniques, including Fourier transform infrared (FT-IR), thermogravimetric, nuclear magnetic resonance (NMR) and UV - visible spectroscopy. The geometries of the formed compounds were evaluated by density functional theory, and the results revealed that NTZ-Ru(III) has an octahedral geometry, while NTZ-Au(III) and NTZ-Ag(I) complexes have distorted square planar structures. Binding between the metal complexes and calf thymus DNA (Ct-DNA) has been studied via absorption spectra. Moreover, human albumen serum (HAS) titration has been carried out to test their susceptibility to interact with a major target molecule via absorption and fluorescence spectroscopic techniques. Several in vitro bioassays were performed to evaluate the biological activity, antibacterial potency against E. coli, antioxidant activity and cytotoxicity of the ligand and the obtained complexes. The results showed that complexes Ru(III) and Au(III) have the highest radical scavenging percentage while the Ag(I) demonstrated the greatest antibacterial activity. Moreover, the metal complexes presented potentially effective against E. coli. Furthermore, compared with NTZ-Ag and the free ligand, the in vitro cytotoxicity assay showed that both NTZ-Ru(III) and NTZ-Au(III) exhibited significant anticancer activity against HeLa cells. The efficiency of the novel compounds as antivirals was tested by molecular docking with two COVID-19 receptors to obtain all interaction details.

Theoretical Investigation by DFT and Molecular Docking of Synthesized Oxidovanadium(IV)-Based Imidazole Drug Complexes as Promising Anticancer Agents.

Vanadium compounds have been set in various fields as anticancer, anti-diabetic, anti-parasitic, anti-viral, and anti-bacterial agents. This study reports the synthesis and structural characterization of oxidovanadium(IV)-based imidazole drug complexes by the elemental analyzer, molar conductance, magnetic moment, spectroscopic techniques, as well as thermal analysis. The obtained geometries were studied theoretically using density functional theory (DFT) under the B3LYP level. The DNA-binding nature of the ligands and their synthesized complexes has been studied by the electronic absorption titrations method. The biological studies were carried with in-vivo assays and the molecular docking method. The EPR spectra asserted the geometry around the vanadium center to be a square pyramid for metal complexes. The geometries have been confirmed using DFT under the B3LYP level. Moreover, the quantum parameters proposed promising bioactivity of the oxidovanadium(IV) complexes. The results of the DNA-binding revealed that the investigated complexes bind to DNA via non-covalent mode, and the intrinsic binding constant (Kb) value for the [VO(SO4)(MNZ)2] H2O complex was promising, which was 2.0 × 106 M-1. Additionally, the cytotoxic activity of the synthesized complexes exhibited good inhibition toward both hepatocellular carcinoma (HepG-2) and human breast cancer (HCF-7) cell lines. The results of molecular docking displayed good correlations with experimental cytotoxicity findings. Therefore, these findings suggest that our synthesized complexes can be introduced as effective anticancer agents.

QSAR Modeling, Molecular Docking and Cytotoxic Evaluation for Novel Oxidovanadium(IV) Complexes as Colon Anticancer Agents.

Four new drug-based oxidovanadium (IV) complexes were synthesized and characterized by various spectral techniques, including molar conductance, magnetic measurements, and thermogravimetric analysis. Moreover, optimal structures geometry for all syntheses was obtained by the Gaussian09 program via the DFT/B3LYP method and showed that all of the metal complexes adopted a square-pyramidal structure. The essential parameters, electrophilicity (ω) value and expression for the maximum charge that an electrophile molecule may accept (ΔNmax) showed the practical biological potency of [VO(CTZ)2] 2H2O. The complexes were also evaluated for their propensity to bind to DNA through UV-vis absorption titration. The result revealed a high binding ability of the [VO(CTZ)2] 2H2O complex with Kb = 1.40 × 106 M-1. Furthermore, molecular docking was carried out to study the behavior of the VO (II) complexes towards colon cancer cell (3IG7) protein. A quantitative structure-activity relationship (QSAR) study was also implemented for the newly synthesized compounds. The results of validation indicate that the generated QSAR model possessed a high predictive power (R2 = 0.97). Within the investigated series, the [VO(CTZ)2] 2H2O complex showed the greatest potential the most selective compound comparing to the stander chemotherapy drug.

Complexation of uranyl (UO2)2+ with bidentate ligands: XRD, spectroscopic, computational, and biological studies.

Three new uranyl complexes [(UO2)(OAc)2(CMZ)], [(UO2)(OAc)2(MP)] and [(UO2)(OAc)2(SCZ)] were synthesized and characterized by elemental analysis, FT-IR, UV-Vis spectroscopy, powder XRD analysis, and molar conductivity. The IR analysis confirmed binding to the metal ion by the sulfur and ethoxy oxygen atoms in the carbimazole (CMZ) ligand, while in the 6-mercaptopurine (MP) ligand, the sulfur and the N7 nitrogen atom of a purine coordinated binding to the metal ion. The third ligand showed a 1:1 molar ratio and bound via sulfonamide oxygen and the nitrogen of the pyrimidine ring. Analysis of the synthesized complexes also showed that acetate groups had monodentate binding to the (UO22+). Density Functional Theory (DFT) calculations at the B3LYP level showed similar structures to the experimental results. Theoretical quantum parameters predicted the reactivity of the complexes in the order, [(UO2)(OAc)2(SCZ)] > [(UO2)(OAc)2(MP)]> [(UO2)(OAc)2(CMZ)]. DNA binding studies revealed that [(UO2)(OAc)2(SCZ)] and [(UO2)(OAc)2(CMZ)] have the highest binding constant (Kb) among the uranyl complexes. Additionally, strong binding of the MP and CMZ metal complexes to human serum albumin (HSA) were observed by both absorbance and fluorescence approaches. The antibacterial activity of the complexes was also evaluated against four bacterial strains: two gram-negative; Escherichia coli and Klebsiella pneumonia, and two gram-positive; Staphylococcus aureus and Streptococcus mutans. [(UO2)(OAc)2(MP)] had the greatest antibacterial activity against Klebsiella pneumonia, the gram-positive bacteria, with even higher activity than the standard antibiotic. In vitro cytotoxicity tests were also performed against three human cancer lines, and revealed the most cytotoxic complexes to be [(UO2)(OAc)2(SCZ)], which showed moderate activity against a colon cancer cell line. Thus, uranyl addition enhances the antibacterial and anticancer properties of the free ligands.

Practical and Computational Studies of Bivalence Metal Complexes of Sulfaclozine and Biological Studies.

In the search for novel, metal-based drug complexes that may be of value as anticancer agents, five new transition metal complexes of sulfaclozine (SCZ) with Cu(II), Co(II), Ni(II), Zn(II), and Fe(II) were successfully synthesized. The chemical structure of each complex was characterized using elemental analysis (CHN), IR spectroscopy, UV-Vis spectroscopy, thermogravimetric analysis (TGA), and electronic paramagnetic resonance (EPR) spectroscopy. IR spectra indicated that the donor atoms were one sulfonyl oxygen atom and one pyrazine nitrogen atom, which associated with the metal ions to form a stable hexagonal coordination ring. The metal-ligand stability constant (Kf) revealed that Cu(II) and Ni(II) have good coordination stability among the metal compounds. Theoretical studies using DFT/B3LYP were performed to further validate the proposed structures. The obtained results indicated that Cu(II) has a trigonal bipyramidal geometry, whereas Fe(II), Co(II), and Ni(II) have an octahedral structure, while Zn(II) has a tetrahedral arrangement. The bio-activities of the characterized complexes were evaluated using DNA binding titration and molecular docking. The binding constant values for the metal complexes were promising, with a maximum value for the copper metal ion complex, which was 9 × 105 M-1. Molecular docking simulations were also carried out to evaluate the interaction strength and properties of the synthesized metal complexes with both DNA and selected cancer-relevant proteins. These results were supported by in vitro cytotoxicity assays showing that the Cu(II) and Ni(II) complexes display promising antitumor activity against colon and breast cancer cell lines.

Lossen Rearrangement of p-Toluenesulfonates of N-Oxyimides in Basic Condition, Theoretical Study, and Molecular Docking.

The sulfonic esters of N-oxyimides are a group of compounds with a wide range of biological activities, as well as a unique reactivity toward amines. They undergo this reaction with primary amines and other nucleophilic reagents according to a Lossen-like rearrangement. The reaction is initiated by nucleophilic attack on a carbonyl group in the succinimide ring followed by isocyanate formation, which next interacts with another nucleophile molecule forming an addition product (e.g., ureido or urethane derivative). However, the secondary amines are also susceptible to other reactions leading to products containing the maleimide ring formed by sulphonic acid elimination. In the case of tertiary amines, this reaction is predominant. To explain the phenomenon of the reactivity of the N- oxyimides toward different types of amines, we employed various spectroscopic and X-ray approaches as well as DFT calculation. Results suggest that the basicity of the amine used for the reaction plays a crucial role in the reaction mechanism that eventually dominates the entire chemical process. Moreover, we applied molecular docking to investigate the ability of the products to act as serine protease inhibitors using human leukocyte elastase (HLE).