Computational analysis of substituent effect on indole derivatives as potential antibacterial agents

Abstract

In recent years, indole derivatives have gained attention as an important class of antimicrobial drugs. The modification of 1,3,4-oxadiazole and 1,2,4-triazole, which are known bioactive agents, was carried out with indole. The resulting compounds namely 3-(1H-indole-3yl)-5-((2-((5-phenyl-1,3,4-oxadiazole-2-yl)thio)ethyl)thio)-4H-1,2,4-triazole-4-amine (S) and 2-(5-(benzylthio)-4H-1,2,4-triazole-3yl)-1H-indole (B) were further investigated for their chemical reactivity with 14 different substituents at the phenyl ring using the density functional theory (DFT). The quantum chemical data used to investigate the most effective drug was based on the optimized geometries, molecular electrostatic potential maps, frontier molecular orbital distributions, Hirschfeld charges, Mulliken charges and UV absorption parameters obtained from DFT calculations. Reduced density gradient (RDG) scatter plots and non-covalent interaction isosurfaces were obtained to visualize the intramolecular interactions in the molecules. Based on the DFT calculations, S14 (-NO2 substituted S) and B14 (-NO2 substituted B) exhibited a better chemical activity. Further, the pertinency of S14 and B14 was tested as an antibacterial agent against E. coli using molecular docking studies. The binding affinity of S14 and B14 showed significant binding with the active sites of the E. Coli macromolecule (PDB id- 2Y66). The boiled egg model was also analyzed to study the permeability and lead likeness of the molecules under investigation. From the synthetic accessibility score, the synthetic feasibility of S14 and B14 was analyzed.