[3+2] Cycloaddition mediated synthesis of spirooxindole pyrrolidine/piperidine fused chromene aldehyde derivatives: DFT studies, antibacterial evaluation and molecular docking investigation as DNA gyrase inhibitors

Abstract

The present work reports the facile synthesis and characterization of a series of diverse 2′-oxo-6b,7,8,9-tetrahydro-6H-spiro[chromeno[3,4-a]pyrrolizine-11,3′-indoline]-6a(11aH)-carbaldehyde derivatives following 1,3-dipolar cycloaddition reaction. This one-pot three-component synthesis involves 2H-chromene-3-carbaldehyde, isatin and secondary amino acids (L-proline/pipecolinic acid) in ethanol to produce the corresponding cycloadducts by conventional and microwave irradiation methods. To determine the regio and stereoselectivity of the product and investigate the mechanism, density functional theory (DFT) studies were done along with ¹H, ¹³C-NMR, DEPT, COSY, NOESY and HRMS. The cycloaddition is found to proceed via four different closely lying transition states as predicted by DFT studies and thermochemical analysis. Furthermore, natural bond orbital (NBO) analysis has been employed to confirm that the cycloaddition follows a radical mechanism. The reaction was found to undergo meta-regioselectivity/endo-stereoselectivity via the most favoured pathway. The synthesized compounds were assessed for in vitro antibacterial activity against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria, using ciprofloxacin as the standard. Compound 16a demonstrated significant inhibitory effects on E. coli and S. aureus, with a zone of inhibition (ZI) of 17 mm and a minimum inhibitory concentration (MIC) of 6.25 μg mL⁻¹ for each of the strains. Additionally, an in silico docking study was conducted to look into the active binding mode of the synthesized compounds within the target enzyme. Structural analysis and molecular docking revealed enhanced binding to bacterial DNA gyrase (E. coli: PDB ID: 1KZN, S. aureus: PDB ID: 3G7B) with a binding affinity of −8.3 kcal mol⁻¹ for compound 16a. In silico ADME predictions suggested favorable pharmacokinetic properties, indicating the potential of these compounds as oral antibacterial drug candidates.