Design, Synthesis, and Biological Evaluation of Pyrimido[4,5- b]indole Derivatives with Potent Activity against Multidrug-Resistant Gram-Negative Bacteria

  • J Med Chem. 2026 Apr 23;69(8):9457-9488. doi: 10.1021/acs.jmedchem.6c00278.
Yuzhi Liu  1  2 ,  Xin-Yu Leng  1  2 ,  Haiqiao Wang  1  2 ,  Shanghan Ruan  1  3 ,  Xin Meng  1 ,  Tiansong Li  4 ,  Haifeng Cao  4 ,  Ying Fu  4  5 ,  Yushe Yang  1  2  3
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4. Department of Chemistry, College of Arts and Sciences, Northeast Agricultural University, Harbin 150030, China.
  • 5. Key Laboratory of Agricultural Functional Molecule Design and Utilization of Heilongjiang Province, Northeast Agricultural University, Harbin 150030, China.
PMID: 41934398 DOI: 10.1021/acs.jmedchem.6c00278
Abstract

The escalating crisis of antimicrobial resistance (AMR), particularly multidrug-resistant (MDR) Gram-negative Bacterial infections, presents a grave threat to global public health. This urgent unmet medical need underscores the demand for novel Antibiotics capable of overcoming existing resistance mechanisms. The ATP-binding sites of Bacterial type II topoisomerases represent promising therapeutic targets against MDR Gram-negative pathogens. Pyrimido[4,5-b]indole-based compounds (GP-1) are the first reported ATPase inhibitors of DNA gyrase with potent and broad-spectrum Antibacterial activity against both MDR Gram-positive and Gram-negative pathogens; however, they are associated with hERG inhibition and suboptimal pharmacokinetic profiles. To overcome these limitations, we designed a new series of pyrimido[4,5-b]indole-based derivatives using structure-based scaffold modification and CADD-guided optimization. This campaign culminated in the discovery of compound 65, which exhibited potent broad-spectrum Antibacterial activity against MDR Gram-negative bacteria without detectable hERG liability. Moreover, 65 demonstrated improved pharmacokinetic properties, leading to enhanced in vivo efficacy compared to levofloxacin in a murine Infection model.

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