Novel drug-drug salts of enoxacin with enhanced antibacterial activity: Insights from solubility and lipid-water partition coefficient

Abstract

Enoxacin (ENX), a third-generation fluoroquinolone, demonstrates broad-spectrum antibacterial activities and is widely applied for the treatment of various bacterial infections. However, it is challenging to improve its antibacterial activity and drug resistance effects based on solubility changes owing to ENX being categorized as a class II drug in the Biopharmaceutics Classification System (BCS). In this experiment, three novel salts formed between ENX and non-steroidal anti-inflammatory drugs (NSAIDs) involving diclofenac (ENX-DFA), flufenamic acid (ENX-FFA) and niflumic acid (ENX-NFA) were firstly synthesized and then characterized. X-ray diffraction, thermodynamic analysis and infrared spectroscopy confirmed the salt formation. Interestingly, all the new salts demonstrated superior antibacterial activities against Escherichia coli (E. coli), Shigella flexneri (Sh. flexneri), Staphylococcus aureus (S. aureus) and Staphylococcus albicans (S. albus) compared with ENX. Further investigation of the pharmaceutical properties of the three salts revealed that they possessed lower aqueous solubility and intrinsic dissolution compared with ENX but exhibited better solubility than the three NSAIDs. Moreover, our results demonstrated that fluctuations in the solubility of ENX salts were pH-dependent. Thus, the solubility changes of ENX salts were assessed using pH-window diagrams. The order of lipid-water partition coefficient (P) was consistent with antibacterial performance (ENX-FFA > ENX-DFA > ENX-NFA > ENX) and was 2.04, 1.95, and 1.69 times greater than that of ENX, indicating that the higher LogP values of salts with strong cell membrane penetration ability improved the efficacy of the drug to inhibit bacterial growth. In summary, this study provides new insights to elucidate antibacterial effects from solubility and LogP values.