Abstract
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.
Highlights
Diabetes mellitus (DM) is foremost health disorder, growing frequently in developing countries
Docking evaluation was done by assessing atomic contact energy (ACE) values, number of hydrogen bonds (H-bonds), number of π-π bonds and hydrophobic interactions formed between ligand-protein complexes
Interactions formed by DPAA, CPAA, PFA, DPC1, DMC1, DOC1 and standard drugs against AA, C-alpha glucosidase (C-AG), N-alpha glucosidase (N-AG), aldose reductase (AR), GK, glycogen phosphorylase (GP), FBP1, phosphoenolpyruvate carboxykinase (PEPCK), 11β-HSD1, glycogen synthase kinase-3β (GSK-3β), peroxisome proliferator-activated receptor γ (PPAR-γ), phosphatidylinositol 3 kinase (PI3K), p-Akt, dipeptidyl peptidase-IV (DPP IV), and protein tyrosine phosphatase 1B (PTP-1B) are shown in Figures S1–S15, respectively
Summary
Diabetes mellitus (DM) is foremost health disorder, growing frequently in developing countries. Factors responsible for DM include increased deskbound lifestyle, nutrition changeover and rapid urbanization leading to widespread, parallel to rise in obesity (Hu, 2011). DM is Ferrocene and Cadmium Derivatives Anti-diabetic Potential mainly characterized by high blood glucose levels, i.e., hyperglycemia with altered metabolism of carbohydrates, proteins and fats due to reduced insulin secretions or/and insulin action. Type I diabetes is associated with deficiency of insulin due to autoimmune-mediated β cells damage (Tuomi, 2005). Hyperglycemic condition in type I diabetes is controlled by administering exogenous insulin via subcutaneous route. Type II diabetes is associated with relatively reduced levels or/and reduced sensitivity of hepatic, cardiac and fat cell toward insulin action. Patients with type II diabetes rely on synthetic anti-diabetic therapy (Nathan et al, 2009)
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