Investigating the molecular interactions of 11-substituted-1-(4-chlorophenyl)-8H-indolo[3,2-c][1,2,4]triazolo[3,4-a]isoquinolines for Antimicrobial Potential: Synthesis, Spectral, In vitro and In silico study interpretations

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Indole molecules are one of the important scaffolds in the discovery and development of new drugs. We herein described a synthesis of new 11-substituted-1-(4-chlorophenyl)-8H-indolo[3,2-c][1,2,4]triazolo[3,4-a]isoquinoline 6 (a-h). Structures of the newly synthesized compounds were confirmed by making use of spectroscopic techniques like IR, NMR and mass. The DFT calculations were taken for the selected molecules using CAM-B3LYP hybrid functional with a 6–31+g(d) all-electron basis set using the Gaussian 09 package. The drug-likeness calculations were explained for the synthesized derivatives. The compounds 6b, 6c and 6 g exhibited excellent antibacterial, antifungal and anti-TB activities against tested pathogens at MIC 3.125 μg/ml. Furthermore, molecular docking studies of these compounds against S. aureus Gyrase (PDB ID:2XCT), Staphylococcus aureus tyrosyl-tRNA synthetase (PDB ID:1JIJ), and Mycobacterium tuberculosis enoyl reductase (INHA) (PDB ID:4TZK), revealed the potential binding mode of the ligands to the site of the appropriate targets. Finally, drug likeness and SAR studies were disclosed. Lastly, the protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through molecular dynamics simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified.