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

Abstract

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 4b 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 4b exhibited low cytotoxicity against LO₂ cells with no distinct tendency to induce the concerned resistance towards MRSA. The tetrazolyl derivative 4b was preliminarily investigated for the possible mechanism; it was revealed that tetrazolyl derivative 4b could both disrupt the integrity of MRSA membrane and form 4b–DNA supramolecular complex by intercalating into DNA. Moreover, tetrazolyl aloe-emodin 4b could bind with MRSA DNA isomerase at multiple sites through hydrogen bonds in molecular simulation.