Aloe-emodin derived azoles as a new structural type of potential antibacterial agents: design, synthesis, and evaluation of the action on membrane, DNA, and MRSA DNA isomerase

As serious global drug resistance motivated the exploration of new structural drugs, we developed a type of novel structural aloe-emodin azoles as potential antibacterial agents in this work. Some target aloe-emodin azoles displayed effective activity against the tested strains, especially tetrazolyl aloe-emodin <b>4b</b> showed a low MIC value of 2 μg mL^-1 towards MRSA, being more efficient than the reference drug norfloxacin (MIC = 8 μg mL^-1). Also, the active molecule <b>4b</b> exhibited low cytotoxicity against LO₂ cells with no distinct tendency to induce the concerned resistance towards MRSA. The tetrazolyl derivative <b>4b</b> was preliminarily investigated for the possible mechanism; it was revealed that tetrazolyl derivative <b>4b</b> could both disrupt the integrity of MRSA membrane and form <b>4b</b>-DNA supramolecular complex by intercalating into DNA. Moreover, tetrazolyl aloe-emodin <b>4b</b> could bind with MRSA DNA isomerase at multiple sites through hydrogen bonds in molecular simulation.