A facile one-pot synthesis to access unique benzopyranonyl cyanopyrimidinols with multitargeting potential against resistant bacteria

  • Bioorg Med Chem Lett. 2026 Jun 4:139:130704. doi: 10.1016/j.bmcl.2026.130704.
Ping-Ping Duan  1 ,  Li Wang  1 ,  Zhen-Zhen Li  2 ,  Cheng-He Zhou  3
Affiliations
  • 1. Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
  • 2. Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China. Electronic address: [email protected].
  • 3. Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China. Electronic address: [email protected].
PMID: 42248367 DOI: 10.1016/j.bmcl.2026.130704
Abstract

To combat rising antimicrobial resistance, a class of novel cyanopyrimidinols (CPOs) were designed and synthesized via a three-component one-pot reaction strategy. Several prepared CPOs exhibited strong Antibacterial activity against the tested bacteria. Especially, benzopyranonyl CPO 4 demonstrated potent activity against Enterococcus faecalis p1-2007226001 (MIC = 0.001 mM), displaying 6- and 64-fold lower MIC values than norfloxacin (MIC = 0.006 mM) and sulfadiazine (MIC = 0.064 mM). CPO 4 showed negligible hemolysis and lower resistance propensity than norfloxacin. In silico ADME analysis revealed favorable drug-likeness and pharmacokinetics of compound 4. Moreover, the highly active molecule CPO 4 displayed superior in vivo Antibacterial activity to norfloxacin in Galleria mellonella Infection model. Further investigation suggested that CPO 4 could intercalate into DNA to form a CPO 4 - DNA complex, thereby blocking DNA replication, while also disrupting Bacterial metabolism and inducing intracellular protein leakage. These findings highlighted cyanopyrimidinols as novel scaffolds for developing multitargeting Antibacterial agents.

Keywords
Antibacterial; Benzopyranone; DNA; Pyrimidine; Synthesis.
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