Enzyme (α-Glucosidase, α-Amylase, PTP1B & VEGFR-2) Inhibition and Cytotoxicity of Fluorinated Benzenesulfonic Ester Derivatives of the 5-Substituted 2-Hydroxy-3-nitroacetophenones

• Published in: International journal of molecular sciences 2024-11, Vol.25 (22), p.11862
• Main Authors: Olomola, Temitope O, Nkoana, Jackson K, More, Garland K, Gildenhuys, Samantha, Mphahlele, Malose J
• Format: Article
• Language: English
• Subjects: A549 Cells; Acetophenones - chemistry; Acetophenones - pharmacology; alpha-Amylases - antagonists & inhibitors; alpha-Amylases - metabolism; alpha-Glucosidases - chemistry; alpha-Glucosidases - metabolism; Amylases; Animals; Antidiabetics; Bioavailability; Biological activity; Cancer therapies; Carbohydrates; Chemical properties; Coronaviruses; Cytotoxicity; Development and progression; Diabetes; Diffraction; Drug approval; Drug therapy; Drugs; Enzyme inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Esters; Esters - chemistry; Esters - pharmacology; Fluorine; Fluorine compounds; Glucose; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Halogenation; Health aspects; Humans; Hyperglycemia; Hypoglycemic agents; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Insulin resistance; Kinases; Ligands; MCF-7 Cells; Metabolic disorders; Molecular Docking Simulation; Organofluorine compounds; Phosphatases; Physiological aspects; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Proteins; Signal transduction; Structure-Activity Relationship; Type 2 diabetes; Tyrosine; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; X-rays
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms252211862

The prevalence of small multi-target drugs containing a fluorinated aromatic moiety among approved drugs in the market is due to the unique properties of this halogen atom. With the aim to develop potent antidiabetic agents, a series of phenylsulfonic esters based on the conjugation of the 5-substituted 2-hydroxy-3-nitroacetophenones - with phenylsulfonyl chloride derivatives substituted with a fluorine atom or fluorine-containing (-CF or -OCF ) group were prepared. Their structures were characterized using a combination of spectroscopic techniques complemented with a single-crystal X-ray diffraction (XRD) analysis on a representative example. The compounds were, in turn, assayed for inhibitory effect against α-glucosidase, α-amylase, protein tyrosine phosphatase 1 B (PTP1B) and the vascular endothelial growth factor receptor-2 (VEGFR-2) all of which are associated with the pathogenesis and progression of type 2 diabetes mellitus (T2DM). The antigrowth effect of selected compounds was evaluated on the human breast (MCF-7) and lung (A549) cancer cell lines. The compounds were also evaluated for cytotoxicity against the African Green Monkey kidney (Vero) cell line. The results of an in vitro enzymatic study were augmented by molecular docking (in silico) analysis. Their ADME (absorption, distribution, metabolism and excretion) properties have been evaluated on the most active compounds against α-glucosidase and/or α-amylase to predict their drug likeness.