Design and synthesis of new curcumin analogues as hepatoprotectives and antioxidants in liver dysfunction through caspase-3 regulation.

BACKGROUND

Chronic liver disease is a progressive, worldwide health crisis, with its incidence and prevalence increasing annually. It causes progressive liver injury and ultimately fibrosis. Globally, it is responsible for approximately 2 million deaths annually. Despite its growing prevalence, there is currently no approved, highly effective targeted therapy for managing liver dysfunction.

OBJECTIVE

Targeting caspase-3 activity may attenuate hepatocellular injury, reduce inflammation and oxidative stress, and thereby improve liver functional integrity.

METHODOLOGY: Ten cyclic curcumin analogues (2-11) were synthesized, followed by preliminary screening for caspase-3 inhibitory activity. Their structures were confirmed by spectral and microanalytical data. The most active triazole (4) and sulfonamide (5) analogues were further evaluated in vivo to assess their anti-inflammatory, antioxidant, and caspase-3 inhibitory effects in rat liver tissue. Molecular docking study was performed to confirm caspase -3 regulation. Radiation stability study was held.

Results

Analogues 4 and 5 significantly improved biochemical and molecular markers associated with liver dysfunction, including reductions in inflammation, oxidative stress, caspase-3 activity, TNF-α, p53, and Bax levels, alongside modulation of Bcl-2 expression.

CONCLUSION

The triazole analogue 4 and sulfonamide analogue 5 demonstrate promising hepatoprotective activity and may represent stable lead compounds for potential therapeutic management of liver dysfunction.