ABSTRACT
Curcumin possesses broad antioxidant and antidiabetic properties but is limited by poor stability and bioavailability. Structural modification through halogenation and heteroaromatic substitution has been explored to overcome some of these limitations. This study evaluated the antioxidant, antidiabetic and cytoprotective activities of three synthetic chloro‐curcumin derivatives (compounds
1
–
3
) in C2C12 myotubes. Antioxidant capacity was assessed using ferric reducing antioxidant power (FRAP) and diphenyl‐1‐picrylhydrazyl (DPPH) assays. Antidiabetic activities were evaluated by inhibition of α‐amylase, α‐glucosidase and porcine pancreatic lipase. Cytotoxicity was determined using the 3‐(4,5‐dimethylthiazol‐2‐yl)−2,5‐diphenyltetrazolium bromide (MTT) and crystal violet assays. Differentiated C2C12 myotubes were exposed to hyperglycaemic conditions (25 mM
d
‐glucose, 48 h) before treatment with compounds
1
–
3
(6 h) to assess their cytoprotective potential and effects on cellular glucose utilization and uptake. All synthetic chloro‐curcumin derivatives demonstrated antioxidant activity, with compound
1
exhibiting the greatest FRAP (absorbance 0.28 ± 0.02 at 700 nm, 10 µg/mL), significantly higher than ascorbic acid (0.22 ± 0.03) at the same concentration (
p
< 0.0001). Hyperglycaemia significantly reduced C2C12 myotube viability to 66.12% ± 1.47%, whereas treatment with the derivatives restored viability, with compound
3
increasing viability to 92.90% ± 6.77% at 0.25 µg/mL (
p
< 0.0001). All compounds significantly enhanced glucose utilization and uptake, with compound
3
producing the greatest increases to 130.70% ± 1.02% and 152.25% ± 4.25%, respectively, relative to the untreated control (
p
< 0.0001). The derivatives also exhibited moderate α‐amylase and α‐glucosidase inhibitory activities, with α‐amylase inhibition generally comparable to acarbose, while pancreatic lipase inhibition remained comparatively weak relative to orlistat. Structural reengineering of curcumin produced derivatives that exhibit antioxidant, cytoprotective and glucose‐modulating activities in a skeletal muscle cell model, highlighting their potential against oxidative stress‐related metabolic disorders, particularly type 2 diabetes mellitus.