Liu Ke, Xiao Tao, Yang Hongfen, Chen Manyun, Gao Qiwen, Brummel Beau R, Ding Yousong, Huigens Robert W
Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), College of Pharmacy, University of Florida Gainesville Florida 32610 USA
RSC Med Chem. 2023 Jun 6;14(8):1472-1481. doi: 10.1039/d3md00204g. eCollection 2023 Aug 16.
It is of great importance to develop new strategies to combat antibiotic resistance. Our lab has discovered halogenated phenazine (HP) analogues that are highly active against multidrug-resistant bacterial pathogens. Here, we report the design, synthesis, and study of a new series of nitroarene-based HP prodrugs that leverage intracellular nitroreductase (NTR) enzymes for activation and subsequent release of active HP agents. Our goals of developing HP prodrugs are to (1) mitigate off-target metal chelation (potential toxicity), (2) possess motifs to facilitate intracellular, bacterial-specific HP release, (3) improve water solubility, and (4) prevent undesirable metabolism (, glucuronidation of HP's phenol). Following the synthesis of HP-nitroarene prodrugs bearing a sulfonate ester linker, NTR-promoted release experiments demonstrated prodrug released 70.1% of parent after 16 hours (with only 6.8% release without NTR). In analogous experiments, no HP release was observed for control sulfonate ester compounds lacking the critical nitro group. When compared to parent HP compounds, nitroarene prodrugs evaluated during these studies demonstrate similar antibacterial activities in MIC and zone of inhibition assays (against lab strains and clinical isolates). In conclusion, HP-nitroarene prodrugs could provide a future avenue to develop potent agents that target antibiotic resistant bacteria.
开发对抗抗生素耐药性的新策略至关重要。我们实验室发现了对多重耐药细菌病原体具有高活性的卤代吩嗪（HP）类似物。在此，我们报告了一系列基于硝基芳烃的新型HP前药的设计、合成及研究，这些前药利用细胞内硝基还原酶（NTR）进行活化并随后释放活性HP制剂。我们开发HP前药的目标是：（1）减轻脱靶金属螯合（潜在毒性）；（2）拥有促进细胞内、细菌特异性HP释放的基序；（3）提高水溶性；（4）防止不良代谢（如HP酚的葡萄糖醛酸化）。在合成带有磺酸酯连接子的HP - 硝基芳烃前药后，NTR促进的释放实验表明，前药在16小时后释放了70.1%的母体HP（无NTR时仅释放6.8%）。在类似实验中，对于缺乏关键硝基的对照磺酸酯化合物，未观察到HP释放。与母体HP化合物相比，在这些研究中评估的硝基芳烃前药在MIC和抑菌圈试验（针对实验室菌株和临床分离株）中表现出相似的抗菌活性。总之，HP - 硝基芳烃前药可为开发针对抗生素耐药细菌的有效药物提供一条未来途径。
