Development and computational analysis of new alkaloid derivatives as potential inhibitors of the SARS-CoV-2 Mpro

Abstract

This study focused on developing and evaluating new alkaloid derivatives as potential inhibitors of the SARS-CoV-2 main protease (M^pro). Five novel alkaloid derivatives were synthesized using standard organic techniques and characterized via infrared and NMR spectroscopy. Pharmacokinetic properties were assessed using Lipinski's Rule of Five and computational tools. Density Functional Theory calculations and molecular docking with AutoDock Vina were employed to analyse molecular properties and interactions with SARS-CoV-2 M^pro. Anti-aggregation and anticoagulant activities were evaluated using aggregometry and coagulation assays. The synthesized compounds exhibited favourable pharmacokinetic properties, including molecular weights below 500 and suitable polar surface areas for bioavailability. Molecular docking revealed strong binding affinities for M^pro, with binding energies ranging from −7.6 to −8.8 kcal/mol. Compounds 1 and 2 showed significant inhibition of platelet aggregation and anticoagulant activity, prolonging prothrombin and activated partial thromboplastin times at 50 μM concentration. Biological activity analysis indicated moderate to high activity as GPCR ligands and protease inhibitors. The synthesized alkaloid derivatives demonstrated high potential as SARS-CoV-2 M^pro inhibitors with additional anti-aggregation and anticoagulant properties. These findings suggest promise for further development as therapeutic agents against COVID-19, although further research is necessary to understand their mechanisms, safety, and clinical application prospects.