Multifunctional Cinnamic Acid Derivatives.

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Biochemistry

Background:

• Multitarget agents offer therapeutic advantages by addressing complex diseases with single compounds.
• Cinnamic acid derivatives and beta-blockers like propranolol possess diverse biological activities.
• Inhibiting lipoxygenase (LOX) and trypsin is crucial for managing inflammatory and other conditions.

Purpose of the Study:

• To synthesize and evaluate novel cinnamic acid derivatives conjugated with various pharmacophores as potential multitarget agents.
• To assess the inhibitory potential of these compounds against lipoxygenase (LOX), trypsin, and lipid peroxidation.
• To determine the cytotoxicity and explore the molecular interactions of promising candidates.

Main Methods:

• Synthesis of 10 novel cinnamic acid derivatives.
• In vitro evaluation of enzyme inhibition (trypsin, LOX) and lipid peroxidation.
• Cytotoxicity assays.
• Molecular docking studies.

Main Results:

• Compound 2b (phenoxyphenyl cinnamic acid-propranolol conjugate) exhibited potent LOX inhibition (IC50 = 6 μM) and antiproteolytic activity (IC50 = 0.425 μM).
• Compound 1a (simple cinnamic acid-propranolol conjugate) showed superior antiproteolytic activity (IC50 = 0.315 μM) and good LOX inhibition (IC50 = 66 μM).
• Compounds 3a and 3b, derived from methoxylated caffeic acid, displayed promising combined inhibitory and antioxidative activities. The S-isomer of 2b also showed a notable multitarget profile.

Conclusions:

• Novel cinnamic acid derivatives possess significant multitarget potential, particularly in inhibiting LOX and trypsin.
• Compound 2b and its S-isomer represent promising leads for developing new anti-inflammatory and antiproteolytic agents.
• Molecular docking supports the in vitro findings, elucidating the binding mechanisms of LOX inhibitors.