One-pot synthesis and biological evaluation of substituted 7-chloroindolizines as antimicrobial, antioxidant, and anti-inflammatory agents

An efficient one-pot synthetic strategy has been developed for the construction of substituted 7-chloroindolizine derivatives using 4-chloropyridine hydrochloride (1) and substituted phenacyl bromides 2(a-i) as key starting Materials. The reaction proceeds via a cascade cyclization under mild and operationally simple conditions, affording a structurally diverse library of indolizine (4a-l) frameworks excellent to good yields. The synthesized compounds were rigorously characterized by ¹H and ¹³C NMR spectroscopy and high-resolution mass spectrometry (HRMS). Biological evaluation identified two active derivatives, 4g and 4h, with Antibacterial activity against Staphylococcus aureus and Escherichia coli (30% and 90% inhibition, respectively). Both exhibited antioxidant potential, with 4h showing the highest ROS scavenging (61% at 100 µg). In vitro assays further revealed selective COX-2 inhibition by 4h (IC₅₀ = 10.24 µM; SI = 3.09), comparable to celecoxib. The DFT analysis revealed a moderate HOMO-LUMO gap (4.07 eV) with well-defined donor and acceptor regions supporting efficient charge transfer. Global reactivity descriptors classify the molecule as a strong electrophile with notable electron-donating capability, while MEP mapping highlights carbonyl and hydroxyl oxygens as key reactive sites. These electronic features collectively indicate strong potential for biomolecular interaction. Computational studies supported these findings, with docking, MM/GBSA, and 200 ns MD simulations confirming stable, energetically favourable interactions of 4h with COX-2 and S. aureus DHFR. Collectively, these results highlight 4h as a promising scaffold for developing multifunctional anti-infective and anti-inflammatory agents. This work underscores the value of a streamlined synthetic approach for rapidly generating heteroaryl scaffolds with significant therapeutic relevance in antimicrobial, antioxidant and anti-inflammatory drug discovery.

7-Chloroindolizines; Antibacterial; Antioxidant; COX; Molecular docking.