Synthesis of indole-derived heterocycles with antibacterial and antibiofilm activity against methicillin-resistant Staphylococcus aureus: Biological evaluation, and computational investigations.

Abstract

Indole-derived heterocycles have attracted significant attention due to their diverse biological activities and therapeutic potential. In particular, the development of novel compounds targeting bacterial resistance and biofilm formation remains a critical focus in antimicrobial research. A series of five electronically diverse indole-derived compounds (C1 - C5) was synthesized and thoroughly characterized using various spectroscopic techniques. Their antibacterial and antibiofilm activities were evaluated against the USA 300 and AB 459 strains, and compound C4 emerged as the most active derivative, exhibiting antibiofilm activity of 54.66% and 51.77% at 31.25 μg mL-1 against USA 300 and AB 459, respectively, while showing moderate growth inhibition. The compound showed no significant cytotoxicity toward human dermal fibroblasts. To elucidate their electronic properties, density functional theory (DFT) calculations were performed, which indicated that C4 possesses the lowest HOMO-LUMO energy gap, reduced chemical hardness, and higher electrophilicity, suggesting enhanced reactivity and electron transfer capability. Molecular electrostatic potential (MESP) analysis further supported these findings by demonstrating significant charge separation in C4, favouring intermolecular interactions. Molecular docking studies against key bacterial targets, penicillin-binding protein 2a (PBP2a), penicillin-binding protein 3 (PBP3), and sortase A (Srt-A) - revealed that C4 exhibits the strongest binding affinity, particularly, with a - 6.642 of docking score toward PBP2a (PDB ID: 3ZFZ). A 100 ns molecular dynamics simulation of the PBP2a-C4 complex further confirmed the stability of the protein-ligand interaction throughout the simulated trajectory. Overall, the combined experimental and computational results identify C4 as the most active compound in the series, with notable antibiofilm, electronic, and protein-binding properties, warranting further investigation to assess its pharmacological potential.