Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5‑b]indole Derivatives Against Gram-Negative Multidrug-Resistant Pathogens

Due to the poor permeability across Gram-negative bacterial membranes and the troublesome bacterial efflux mechanism, only a few GyrB/ParE inhibitors with potent activity against Gram-negative pathogens have been reported. Among them, pyrimido­[4,5-b]­indole derivatives represented by GP-1 demonstrated excellent broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria but were limited by hERG inhibition and poor pharmacokinetics profile. To improve their drug-like properties, we designed a series of novel pyrimido­[4,5-b]­indole derivatives based on the tricyclic scaffold of GP-1 and the C-7 moiety of acorafloxacin. These efforts have culminated in the discovery of a promising compound 18r with reduced hERG liability and an improved PK profile. Compound 18r exhibited superior broad-spectrum in vitro antibacterial activity compared to GP-1, including a variety of clinical multidrug G– pathogens, especially Acinetobacter baumannii, and the in vivo efficacy was also demonstrated in a neutropenic mouse thigh model of infection with multidrug-resistant A. baumannii.

由于革兰氏阴性菌细胞膜通透性不佳且细菌外排机制较为棘手，目前仅有少数针对革兰氏阴性致病菌具有强效活性的GyrB/ParE抑制剂（GyrB/ParE inhibitors）被报道。其中，以GP-1为代表的嘧啶并[4,5-b]吲哚衍生物（pyrimido[4,5-b]indole derivatives）对革兰氏阳性菌与革兰氏阴性菌均展现出优异的广谱抗菌活性，但存在hERG抑制（hERG）及药代动力学特性欠佳的缺陷。为优化此类化合物的成药性，我们基于GP-1的三环骨架与阿拉沙星（acorafloxacin）的C-7位取代基，设计了一系列新型嘧啶并[4,5-b]吲哚衍生物。经上述研究工作，最终发现了极具潜力的化合物18r：其hERG抑制风险显著降低，药代动力学特性也得到改善。相较于GP-1，化合物18r的广谱体外抗菌活性更优，可有效对抗多种临床分离的多重耐药革兰氏阴性致病菌，尤以鲍曼不动杆菌（Acinetobacter baumannii）为甚；此外，在多重耐药鲍曼不动杆菌感染的中性粒细胞减少小鼠大腿感染模型中，其体内抗菌活性亦得到了验证。