Synthesis, TD-DFT calculations, molecular docking and ADME studies of new spiro-oxindole derivatives containing 5(4H)-oxazolone as anti-viral and anti-bacterial agents

Abstract

Spiro pyrrolidine oxindole and oxazolone compounds have been widely used in medicinal chemistry. They can show anti-viral, anti-diabetic, anti-cancer, anti-bacterial, anti-stress, anti-allergic, and anti-inflammatory effects. The 1,3-dipolar cycloaddition reaction, initiated by the in situ formation of an azomethine ylide, serves as a highly effective synthetic approach for constructing pyrrolidine-appended and pyrrolidine-fused heterocycles. Herein, efficient synthesis of 5 new derivatives of spiropyrrolidine oxindole framework of azomethin ylied with 4-arylidine- 5(4H)-oxasolone as dipolarophile via the one-pot multicomponent 1, 3-dipolar cycloaddition is reported. The chemical structures of the newly synthesized analogs were determined through an analysis of their spectroscopic data. In continuation, biological activity and reactivity of derivatives of spirooxindole were evaluated using computational chemistry methods such as molecular docking, and density functional theory. Also, their pharmacokinetic properties were investigated to evaluate the risk of toxicity using SWISS ADME and PKCSM online sites. In the investigation of molecular docking, the interaction of five spirooxindole derivatives with 6W63 proteins (the main protease of COVID-19) and 4EMV (ATP topoisomerase inhibitor) was studied to investigate their anti-viral and anti-bacterial properties.Based on the analysis of docking, derivatives d and e have antiviral activity with 6w63 protein and interaction b molecule with 4emv protein shows more suitable antibacterial activity. Study of reactivity descriptors obtained from quantum mechanical calculations showed that the reactivity of all compounds is almost the same and compound c is substituted by fluorine; with the formula C₂₆H₂₀FN₃O₃ it is more than other compounds. Pharmacokinetic studies showed that all compounds have high digestive and intestinal absorption and low toxicity which is an important parameter for a drug. Molecular docking, ADMET analysis, and TD-DFT analysis are used to assess the drug-likeness of c compound as both antiviral and anti-bacterial agents.

Keywords: 1, 3-Dipolar cycloaddition; Molecular docking; Reactivity; Spiro-oxindole derivatives; Time-dependent density functional theory.