Docking Investigations Targeting Receptors 2AZ5 and 5KIR, along with the Synthesis and Pharmacological Assessment of Derivatives of 7-Hydroxy-4-Methyl Coumarin

Inflammation, a crucial defense mechanism of the immune system, seeks to safeguard and restore tissue equilibrium in response to tissue damage or infection by pathogens. Key indicators of inflammation include redness, discomfort, swelling, warmth, and impaired function. However, unmanaged inflammation can lead to serious health issues.

The aim of this research work is to perform docking studies to find out the potent anti-inflammatory activity of various moieties (Schiff bases, hydrazones, and amino acid) derivatives, which are attached to C-8 of 7-hydroxy-4-methyl coumarins. Also, the synthesized compounds were characterized and their pharmacological evaluation (in-vitro and in-vivo study) was conducted.

Lipinski's Rule of Five assessed drug-likeness for each designed molecule. Molecular docking with COX-2 protein was conducted using AutoDock vina to identify the highest-scoring molecule. Various novel coumarin derivatives, which include Schiff bases, hydrazone, and amino acid derivatives (F, G, and H, respectively) were prepared by inserting the formyl group at the C-8 position of 7- hydroxy-4-methyl coumarin. At first, the docking studies were performed against 2AZ5 and 5KIR receptors to find the activity against inflammation. Also, the compounds with the best dock scores were synthesized and elucidated by FT-IR, ¹H- NMR, and Mass spectroscopy. Moreover, a series of novel derivatives were screened in in-vitro and in-vivo to evaluate the potent anti-inflammatory activity.

All the novel derivatives, which were synthesized have been found to show potent anti-inflammatory activity by in-vitro and in-vivo evaluation. Among all the derivatives, compound F1 showed the highest inhibitory effect against TNF-α and COX-2 enzymes.

Our result exhibited potential anti-inflammatory activity of the novel coumarin compounds, especially the substituted anilines and amino acids at C8 of the coumarin moiety, which works against TNF- α and COX-2 enzyme.