In silico drug evaluation by molecular docking, ADME studies and synthesis, characterization, biological activities, DFT, SAR analysis of the novel Mannich bases

Abstract

In this study, seven new Mannich bases 4a-g, containing 1,2,4-triazole and 2,6-dimethylmorpholine were synthesized and characterized by ¹³C-NMR, ¹H-NMR and IR spectroscopy. Newly synthesized compounds’ antioxidant characteristics were assessed with three different techniques (Reducing Power, Metal Chelation Activity, and Free Radical Scavenging). These compounds were also evaluated for their antimicrobial activity against 6 different bacteria. In vitro studies revealed that the synthesized compounds exhibited high metal chelating activity due to the presence of -OH, C = O, -NR₂, and -O- groups, despite their low free radical scavenging and reducing activity. Furthermore, antibacterial tests revealed that compound 4e, in particular, exhibited potent activity against six different bacterial species, demonstrating its potential as an antimicrobial agent. These results suggest that these compounds possess significant biological activities that may influence both metal ion chelating and microbial growth. These new Mannich bases were evaluated for their drug availability and absorption, distribution, metabolism, and excretion (ADME) properties using the SwissADME tool. ADME analysis results showed that the newly synthesized compounds could find application in the field focused on the production of effective and harmless pharmacological drugs. Molecular docking analysis was performed to investigate the potential Alzheimer’s disease activities of the newly synthesized compounds with BChE (PDB: 6SAM) and GST (PDB: 5J41) enzymes. In molecular docking analysis, compound 4d with enzyme 6SAM (docking score − 9.91) and compound 4e with enzyme 5J41 (docking score − 8.37) among the synthesized compounds showed good results on potential Alzheimer’s disease. In addition, SAR analysis was performed by calculating the HOMO-LUMO, ΔE values of the new compounds with DFT. SAR analysis results were compared with ADME, molecular docking analysis, and antimicrobial activity results. The high metal chelation and antimicrobial activities obtained in this study were consistent with the DFT-based HOMO-LUMO energy differences (ΔE) calculated from the electronic structures of the compounds. In particular, compounds with low energy differences exhibited both high binding affinity to target enzymes in molecular docking studies and effective results in biological assays, demonstrating a strong correlation between experimental findings and theoretical calculations. This consistency demonstrates that the biological activities of compounds are directly related to their molecular electronic properties and that computational approaches can guide the design of effective compounds.