Catalyst‐Free Synthesis of 9 H ‐Fluorene‐Based Petasis Borono–Mannich Adducts: Design, Optimization, Anti‐Inflammatory Activity, and Molecular Docking Studies
TL;DR
Preliminary in silico ADMET assessment indicated generally favorable absorption‐related properties across the series, while also identifying potential toxicity liabilities that require experimental validation.
Abstract
In this study, we report a catalyst‐free Petasis Borono–Mannich approach for the efficient synthesis of novel 9 H ‐fluorene‐based alkyl‐amino derivatives with potential anti‐inflammatory activity. The reaction, involving 2‐fluorenecarboxaldehyde, various secondary amines, and substituted boronic acids, was optimized using 1,4‐dioxane and molecular sieves at 90°C, affording a series of compounds (4a–4o) in excellent yields. Biological evaluation via bovine serum albumin (BSA) denaturation assay revealed promising anti‐inflammatory activity, with compound 4o (IC 50 = 13.02 µM) showing efficacy comparable to diclofenac sodium (IC 50 = 12.11 µM). Structure–activity relationship (SAR) analysis indicated N ‐methylpiperazine and electron‐donating aryl boronic acids as key contributors to potency. Molecular docking against COX‐1 identified compound 4o as having the most favorable predicted docking score (−10.2 kcal/mol). Additionally, 100 ns molecular dynamics simulation of the lead 1EQG– 4o complex provided further insight into its conformational behavior and residue‐level flexibility under dynamic conditions. Preliminary in silico ADMET assessment indicated generally favorable absorption‐related properties across the series, while also identifying potential toxicity liabilities that require experimental validation.