Green synthesis, density functional theory (DFT), molecular docking, molecular dynamics simulation and biological activity of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives as PLA2 and proteinase K inhibitors

Abstract

In diseases like atherosclerosis, rheumatoid arthritis, and sepsis, phospholipase A2 (PLA2) and proteinase K play a role in inflammation by releasing arachidonic acid (AA). The crucial step in the inflammatory process is believed to be the release of prostaglandins after PLA2 mobilizes AA. Drugs obstructing the COX and LOX pathways in the arachidonic acid cascade, drugs that inhibit these enzymes can treat inflammatory processes. To combat against these inflammatory promoters,the authors herein report an effective method for the synthesis of a series of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives (4a–h) under the effect of TiO2 as a photocatalyst in ethanolic medium, and their effect against phospholipase A2, as well as proteinase K, was evaluated. The results confirmed that using TiO2 (20 mg) as a photocatalyst exhibits excellent performance in terms of yield and reaction time. The yield of all the synthesized compounds is between 79 and 91 % in just 60 min. After closely evaluating the SAR of the examined compounds against both enzymes, it was discovered that compounds (4b, 4f) with electron-donating substituents have higher PLA2 inhibitory (%) activity than those with electron-removing substituents (4a, 4e). Compounds (4c, 4d) containing heterocyclic rings showed significantly higher proteinase inhibitory (%) activity when compared to other electron-donating or withdrawing compounds. It was further confirmed that studied compounds against both enzymes exhibited dose-dependent behavior. We studied the intermolecular interactions of the compounds by molecular docking with human non-pancreatic secretory phospholipase A2 and proteinase K. We evaluated the dynamical stability of the docked complexes using a 100 ns molecular dynamics simulation, which revealed stable interactions based on root mean square deviation/fluctuation (RMSD/RMSF), radius of gyration, Gibbs free energy landscapes, and principal component analyses (PCA). Moreover, the ADME properties of the compounds align with Lipinski’s rule of five, suggesting their potential as viable candidates for the development of therapies against inflammatory diseases. All compounds tested inhibited PLA2 more than proteinase K. However, compounds 4b and 4f better inhibited phospholipase A2, whereas compounds 4c and 4d showed better activity against proteinase K.