Dual COX-2/5-LOX Inhibition by Novel Thymol Derivatives: From Molecular Modeling to In Vitro Validation

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Classical nonsteroidal anti-inflammatory drugs (NSAIDs) carry risks; dual cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) inhibitors offer a safer alternative for inflammation management.
• Thymol derivatives are explored to enhance bioactivity, selectivity, stability, and pharmacokinetic properties for improved anti-inflammatory effects.

Purpose of the Study:

• To design and synthesize novel thymol derivatives targeting both COX-2 and 5-LOX active sites.
• To evaluate the anti-inflammatory potential of modified thymol compounds through molecular modeling and in vitro assays.

Main Methods:

• Molecular docking and molecular dynamics simulations were employed to guide ligand design.
• Synthesis and in vitro evaluation of thymol derivatives, including halogenated and succinate forms (T, FT, BT, T1, T2, T3).
• Analysis of ligand interactions with COX-2 and 5-LOX active sites and cavity analysis for COX-2 entry site.

Main Results:

• Molecular modeling indicated favorable interactions of designed ligands with COX-2 and 5-LOX, identifying T1-T3 as promising candidates.
• In vitro assays revealed T3 as the most potent COX-2 inhibitor and T2 as the most effective 5-LOX inhibitor.
• T3's favored insertion into the COX-2 entry site was attributed to its polarity and hydrogen bonding capability.

Conclusions:

• Novel thymol derivatives, particularly T2 and T3, demonstrate significant potential as dual COX-2/5-LOX inhibitors.
• These compounds represent promising safer alternatives to traditional NSAIDs for managing inflammatory conditions.
• The study highlights the successful integration of computational modeling and in vitro validation in drug discovery.