Faiza Asghar

Facile synthesis of fluoro, methoxy, and methyl substituted ferrocene-based urea complexes as potential therapeutic agents

In the present work, the synthesis, characterization (FT-IR, multinuclear (1H and 13C) NMR, AAS, Raman, and elemental analysis), DNA binding (cyclic voltammetry, UV-Vis spectroscopy and viscometry), and in vitro biological assessment of nine new ferrocene-based ureas are reported. The desulphurization of ferrocenyl thioureas to the corresponding oxo analogues using aqueous sodium hydroxide and mercuric chloride led to the ferrocenyl ureas (F1-F9) in high yields. The DNA binding studies performed by cyclic voltammetry and UV-Vis spectroscopy produced results that are in close agreement with one another for the binding constants (K) and an electrostatic mode of interaction was observed. The nature and the extent of interaction with DNA was further investigated by viscometry. The DFT/B3LYP method was used to determine the charge distribution and HOMO/LUMO energies of the optimized structure. The DFT calculated HOMO and LUMO energies correlate well with the experimentally determined redox potential values. The synthesized ferrocenyl derivatives exhibited good scavenging activity against 1,1-diphenyl-2-picrylhydrazyl radical (DPPH). These complexes were also scanned for their in vitro cytotoxicity against human carcinoma cell line THP-1 (leukemia cells). The results showed a moderate level of cytotoxicity against the subjected cancer cell line as compared with the standard chemotherapeutic drug (cisplatin).

Antileishmanial, DNA Interaction, and Docking Studies of Some Ferrocene‐Based Heteroleptic Pentavalent Antimonials

A series of ferrocenyl pentavalent antimonials (1–8) were synthesized and characterized by elemental analysis, FT‐IR, and multinuclear (1H and 13C) NMR spectroscopy. These antimonials were evaluated for their antileishmanial potential against Leishmania tropica KWH23, and by biocompatibility and membrane permeability assays. Moreover, mechanistic studies were carried out, mediated by DNA targeting followed by computational docking of ferrocenyl antimonials against the leishmanial trypanothione reductase enzyme. It was observed that the antimonials 1–8 were 390‐fold more efficacious (IC50) as compared with the standard antimonial drug used. Cytotoxicity results showed that these antimonials are highly active even at low concentrations and are biocompatible with human macrophages. Antimonials 1–8 exhibited extensive intercalation with DNA and, furthermore, docking interactions highlighted the potential interactive binding of the anitimonials within the trypanothione reductase active site, with van der Waals interactions contributing significantly to the process. Hence, it is suggested that the reported antimonials demonstrate high efficacy, less toxicity, and target multiple sites of the Leishmania parasite.

Computational and Pharmacological Evaluation of Ferrocene-Based Acyl Ureas and Homoleptic Cadmium Carboxylate Derivatives for Anti-diabetic Potential

We investigated possible anti-diabetic effect of ferrocene-based acyl ureas: 4-ferrocenyl aniline (PFA), 1-(4-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DPC1), 1-(3-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DMC1), 1-(2-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DOC1) and homoleptic cadmium carboxylates: bis (diphenylacetato) cadmium (II) (DPAA), bis (4-chlorophenylacetato) cadmium (II) (CPAA), using in silico and in vivo techniques. PFA, DPC1, DMC1, DOC1, DPAA and CPAA exhibited high binding affinities (ACE ≥ −350 Kcal/mol) against targets: aldose reductase, peroxisome proliferator-activated receptor γ, 11β-hydroxysteroid dehydrogenase-1, C-alpha glucosidase and glucokinase, while showed moderate affinities (ACE ≥ −250 Kcal/mol) against N-alpha glucosidase, dipeptidyl peptidase-IV, phosphorylated-Akt, glycogen synthase kinase-3β, fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase, whereas revealed lower affinities (ACE < −250 Kcal/mol) vs. alpha amylase, protein tyrosine phosphatases 1B, glycogen phosphorylase and phosphatidylinositol 3 kinase. In alloxan (300 mg/Kg)-induced diabetic mice, DPAA and DPC1 (1–10 mg/Kg) at day 1, 5, 10, 15, and 20th decreased blood glucose levels, compared to diabetic control group and improved the treated animals body weight. DPAA (10 mg/Kg) and DPC1 (5 mg/Kg) in time-dependent manner (30–120 min.) enhanced tolerance of oral glucose overload in mice. DPAA and DPCI dose-dependently at 1, 5, and 10 mg/Kg decreased glycosylated hemoglobin levels in diabetic animals, as caused by metformin. These results indicate that aforementioned derivatives of ferrocene and cadmium possess anti-diabetic potential.

Biologically active halo-substituted ferrocenyl thioureas: synthesis, spectroscopic characterization, and DFT calculations

In our search for new therapeutic agents, ferrocene-based thioureas (M1–M9) were successively synthesized and characterized by various analytical techniques like FT-IR, Raman, CHNS, AAS, and multinuclear (1H and 13C) NMR. The interaction of the compounds with DNA was investigated by electrochemical and spectroscopic measurements. These complexes exhibited impressive binding constants ranging from 9.75 × 103 to 5.71 × 104 M−1. The diffusion coefficients of the drug–DNA adducts are lower than that of the free drug indicating the formation of a high molecular weight complex that diffuses slowly towards the electrode. The cathodic peak potential shift in the cyclic voltammetric behavior of the synthesized complexes by the addition of DNA is attributable to the electrostatic interactions between the compound and DNA, an indicator of the oxidizable behavior of the compounds in the presence of the negative environment of DNA. The energies of the frontier molecular orbitals (EHOMO and ELUMO) and the Mulliken charge distribution on the optimized structures were determined using the DFT/B3LYP method combined with the 6-31G(d,p) basis set in DMSO. The theoretically calculated HOMO and LUMO energies (HOMO–LUMO band gap) based on the DFT study correlate well with the electrochemically determined redox potentials (electrochemical band gap), having a correlation coefficient of 0.953. The synthesized thioureas were preliminarily screened for their in vitro antimicrobial and cytotoxic activities. However, the most significant antitumor activity was found for M3 with an IC50 value of 1.87 μM. These compounds played a significant role in arresting microbial growth. The computational measurements were found to be in close agreement with the outcomes of biological activities.