Synthesis and structure-activity relationships of indole-3-butyric acid-based hydrazones: predicting their antibacterial and antioxidant potential through integrated experimental, molecular docking and DFT studies.

Indole-based hydrazone derivatives are a valuable group of molecules owing to their adjustable electronic structures, strong donor-acceptor properties, and broad biological applications in antioxidants, antibacterials, and optoelectronics. In the current work, indole 3-butyric acid (IBH) derivatives of hydrazones (DHIBH, PIBH, NIBH, MBIBH, 4-MBIBH, ICIBH, 4-PCIBH, and TCIBH) were prepared using a multi-step method with aldehydes or ketones substituted to form the hydrazide group. Melting point analysis and FTIR, UV-visible and NMR spectroscopy confirmed the structures of the hydrazine derivatives. The evaluation of biological activity showed trends in activity. DHIBH outperformed all other compounds synthesized in terms of antibacterial screening against Escherichia coli and Staphylococcus aureus, with maximum zones of inhibition of 18.3 mm and 19.3 mm, respectively, and an MIC of 2.5 mg mL-1. Meanwhile, ICIBH and 4-PCIBH exhibited selective performance against the Gram-positive strain at a dosage of 2.5 mg mL-1, while the antioxidant activity was observed using the DPPH assay, with DHIBH being the most effective radical scavenger with an IC50 of 44.51 ± 7.46 µL mL-1. The findings of the experiment were justified by extensive DFT computations. There was good agreement between the experimental vibrational frequencies and the calculated vibrational frequencies, which verified the structural stability and functional group integrity of the structure using comparative IR analysis. Frontier molecular orbital analysis has shown that the HOMO-LUMO energy gaps are substituent-dependent, which shows variable chemical reactivity and charge-transfer capacity. UV-vis analysis favors the predominant π → π and n → π transitions with the bathochromic effects of extended conjugation and electron-withdrawing substituents, respectively. Nonlinear optical (NLO) computations proved an increase in the dipole moment, polarizability, and first hyperpolarizability of a few derivatives, which denoted their multifunctional behavior. Molecular electrostatic potential, global reactivity descriptors, and NBO analyses were further used to provide greater insights into and confirm the presence of efficient intramolecular charge transfer. A strong correlation between molecular docking with DNA gyrase B (PDB ID: 6F86) and antioxidant-related protein (PDB ID: 1HD2) was observed against experimental antibacterial and antioxidant data, especially with DHIBH and NIBH. The ADMET results confirmed the favorable drug-like and pharmacokinetic properties of all the compounds. In general, these findings indicate that indole-based hydrazones are promising lead structures that should be further optimized structurally and biologically prior to the determination of their therapeutic potential.