Design, synthesis, anti-MRSA activity evaluation, and mechanism of action study of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivatives

  • Eur J Med Chem. 2026 Jul 8:317:119127. doi: 10.1016/j.ejmech.2026.119127.
Qing-Jie Zhang  1 ,  Yu-Xi Li  1 ,  Ying-Xu Yan  1 ,  Ri-Fei Gu  2 ,  He-Chao Zhang  1 ,  An-Ji Zhu  1 ,  Wen-Bo Ge  1 ,  Xiao Xu  1 ,  Ya-Jun Yang  1 ,  Xi-Wang Liu  3 ,  Jian-Yong Li  4
Affiliations
  • 1. Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China.
  • 2. College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China.
  • 3. Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China. Electronic address: [email protected].
  • 4. Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China. Electronic address: [email protected].
PMID: 42430954 DOI: 10.1016/j.ejmech.2026.119127
Abstract

Currently, methicillin-resistant Staphylococcus aureus (MRSA) resistance is becoming increasingly severe, leading to a decline in the efficacy of existing antimicrobial agents. Consequently, there is an urgent need to develop novel anti-MRSA drugs. During the development of novel dihydrofolate reductase (DHFR) inhibitors, it was found that several derivatives based on the 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline (PQD) scaffold exhibited potent Antibacterial activity. Thus, 28 PQD derivatives were designed, synthesized, and structurally characterized in this study. Among them, the active molecule A13 demonstrated potent Antibacterial activity against Staphylococcus aureus (S. aureus), clinical S. aureus isolates, and MRSA (MICs = 0.008-0.063 μg/mL), while exhibiting low hemolytic activity (HC50 > 64 μg/mL) and moderate cytotoxicity (IC50 = 4.092-5.347 μg/mL). In addition, A13 exhibited rapid bactericidal properties and potent anti-biofilm activity. Mechanistic studies demonstrated that A13 accelerated Bacterial death by disrupting the integrity of the cell membrane and inhibiting DHFR. Furthermore, A13 exhibited significant therapeutic efficacy in a mouse skin abscess model induced by MRSA. In summary, the active molecule A13 may be a promising candidate for the treatment of MRSA infections.

Keywords
Antibacterial activity; DHFR; MRSA; PQD; Synthesis.
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