2‐Hydroxypropyl Group Linked Derivatives of Indole Azoles as Potential Multifunctional Antibacterial Candidates for Effectively Inhibiting the Activity of MRSA and Responding Inflammatory Factors

Abstract

AbstractThe increasing resistance of methicillin‐resistant Staphylococcus aureus (MRSA) to antibiotics has led to escalating efforts to design and synthesize new structural agents with significant antimicrobial potential. A novel class of 2‐hydroxypropyl group linked derivatives of indole azoles was developed as potential antibacterial agents. Bioactivity screening results demonstrated that metronidazole‐modified indole derivative 4 a had excellent antibacterial capacity against MRSA (MIC=6 μM), which was about 4 times that of norfloxacin (MIC=25 μM). Highly active hybrid 4 a did not cause obvious drug‐resistance in MRSA after multiple generations (15 passage operations). Compound 4 a showed low toxicity to normal mammalian cells (RAW 264.7). Molecular docking and molecular electrostatic potential (MEP) surface studies were used to map hydrogen bond interactions and the electron distribution in the highly active compounds. In addition, the preliminary exploration of the antibacterial mechanism revealed that the active molecule 4 a could infiltrate the membrane of MRSA and insert into MRSA DNA to prevent its replication, thus activating strong inhibition of the bacteria. Furthermore, highly active derivative 4 a could better respond to inflammatory factors (IL‐6, IL‐10, TNF‐α and PGE‐2), and it is less likely to cause inflammatory complications, hence diversifying the functions of antibacterial candidate molecules. These findings effectively indicate the potential of the bioactive hybrid 4 a as a multifunctional anti‐MRSA agent. Further exploration of the development of antimicrobials combining these kinds of 2‐hydroxypropyl group linked indole derivatives is of great value.