Microwave-assisted green synthesis and structural characterization of N-aryl pyrrole derivatives via Mn-catalyzed Clauson-Kaas reaction: DFT, NMR correlation, and bioactivity evaluation

The present work reports the synthesis of a library of nineteen N-aryl pyrrole derivatives via a microwave-assisted, manganese-catalyzed Clauson–Kaas reaction. Among them, Bis (4-(1H-pyrrol-1-yl)phenyl) methane ( 3c ) displayed the highest molecular docking affinity toward EGFR (−9.5 kcal/mol) and CDK-2 (−8.8 kcal/mol), as compared to co-crystallized ligands. For confirming the structures, we performed the DFT studies and among them, the geometry optimizations were carried out using the B3LYP functional with PCM (chloroform) in the Jaguar module of the Schrödinger Suite, employing the 6–311++G(d,p) basis set for most compounds and DEF2-SV(P) for halogen-containing derivatives. PES scans (B3LYP-D3 level) revealed global minima conformers of all the 19 compounds. The compound ( 3c ) exhibited its most stable conformation at a dihedral angle of 300° between phenyl rings. The NMR chemical shift predictions (B3LYP-D3/LACVP) on these PES-optimized structures were closely correlated with experimental values (RMSD: 0.2–1.0 ppm for 1 H, 0.5–1.6 ppm for 13 C)). ADME studies using SwissADME and ADMETlab 3.0 revealed favourable pharmacokinetics, including high GI absorption for ( 3c ). Toxicity prediction using ProTox-3.0 classified ( 3c ) in class 4 (LD₅₀ = 1830 mg/kg) with minimal ecological risk. In vitro MTT assay in non-small lung cancer cell line (NSLC) of NCI-H460 further confirmed its anticancer activity (IC₅₀ = 67.31 μg/mL). These results suggest compound ( 3c ) as a promising anticancer candidate with strong target affinity and drug-like behaviour.