Identification of novel 4-thiazolidinones as new TcaR inhibitors: Design, synthesis, molecular docking, MD simulation, ADMET and in vitro antibacterial evaluation

Abstract

Novel morpholine and piperazine-containing 4-thiazolidinone derivatives (6a-6e) and (7a-7e) were designed and synthesized utilizing a multi-component reaction (MCR) to develop lead compounds with excellent antibacterial potency. The synthesized compounds were characterized using various analytical techniques, including 1H NMR, 13C NMR, IR and HR-MS. Additionally, the docking studies against microbial transcriptional regulators (TcaR) protein offered a comprehensive understanding of the binding interactions between potential molecules and the 3KP3 protein of the Staphylococcus epidermidis (RP62A) organism. These docking studies enabled the prediction of the binding affinity and the identification of key molecular interactions between the compounds and the target protein. Derivatives 6b and 6d showed excellent in vitro inhibitory action at par with ampicillin against S. pyogenes and E. coli, respectively. In general, piperazine-containing compounds showed greater affinity to bind with target protein than the morpholine-containing compounds. The probable reason being, the salt bridge is formed using a terminal nitrogen of the piperazine substituent with the target protein. Furthermore, to assess the dynamic behavior and stability of the most promising compound 6b in complex with the target protein, molecular dynamics simulations were conducted. Protein Cα atoms' RMSD figure reveals that the complex was stable throughout the simulation since the deviation was not more than 2.7 Å at any one time. The simulations revealed that the compound maintained its favorable binding conformation throughout the trajectory, indicating a strong and persistent interaction with the target protein. The in silico ADMET studies of synthesized compounds suggest all compounds are nontoxic and non-carcinogenic in the biological systems.