Synthesis and Bio-evaluation of the p-(Arylsulfonylbenzene)carbaldehyde 4-(Trifluoromethylphenyl) Hydrazones as Anti-hyperglycemic Agents with Anti-inflammatory, Cytotoxic and Antioxidant Effects

• The p -(arylsulfonylbenzene)carbaldehyde arylhydrazones exhibited dual α-glucosidase and α-amylase activity • Some of the derivatives also exhibited inhibitory effect against LOX-5 • The compounds exhibited moderate antigrowth effect against the MCF-7 cell line • The compounds exhibited promising antioxidant effects by suppressing LPS-induced ROS in the MCF-7 and Hek293-T cell lines • Molecular modelling studies provided insights into the binding interactions and drug-like properties of these compounds It is envisaged that drugs which could reduce hyperglycemia and at the same time mitigate inflammatory processes and oxidative stress with reduced side effects, or no toxicity could offer an opportunity for the development of novel multifunctional therapeutics for diabetic patients. This work presents the rational design, synthesis, and comprehensive in vitro and in silico biological evaluation of a novel series of arylsulfonylbenzene carbaldehyde arylhydrazone hybrids 3a – p as nitrogen- and halogen-enriched molecular architectures with potential to serve as multifunctional agents against some of the biochemical targets linked to type 2 diabetes mellitus (T2DM). Compounds 3b, 3c in category 3a – h and the series 3i – p with increased inhibitory effect against α-glucosidase (IC 50 = 3.38 – 8.07 µM) compared to acarbose (IC 50 = 9.95 µM) were further assessed for activity against α-amylase and lipoxygenase-15 (LOX-15), and for cytotoxicity against the breast cancer (MCF-7) cell line and the human embryo kidney derived (Hek293-T) cell line. Selected compounds were subjected to an in vitro cell-based antioxidant activity assay involving lipopolysaccharide (LPS) induced reactive oxygen species (ROS) production in MCF-7 and Hek293-T cells. Molecular docking predicted the hydrazone linker as a critical anchoring point within the catalytic site of the test enzymes and the sulfonyl group as a hydrogen bond acceptor with the aromatic rings engaged in π-π stacking interactions and van der Waals contacts that reinforce binding. Additionally, their ADMET (absorption, distribution, metabolism, excretion and toxicity) properties were predicted using an in silico method and molecular dynamics simulations conducted on representative models to examine the stability of the protein-ligand complex over time.