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Design, synthesis, and evaluation of N1,N3-dialkyldioxonaphthoimidazoliums as antibacterial agents against

Taewoo Kim1, Shin-Yae Choi2, Hee-Won Bae2

  • 1College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, 120 Haeryong-ro, Pocheon-si, Gyeonggi-do 11160, Republic of Korea.

European Journal of Medicinal Chemistry
|May 5, 2024
PubMed

Insights

Researchers developed a new compound, N1,N3-n-octylbenzyldioxonaphthoimidazolium bromide (11), showing potent activity against antibiotic-resistant bacteria like MRSA. This novel agent demonstrated efficacy in vivo without inducing bacterial resistance, offering a promising new avenue for combating drug-resistant infections.

Area of Science:

  • Medicinal Chemistry
  • Antimicrobial Agents
  • Drug Discovery

Background:

  • Antibiotic resistance, particularly from Methicillin-resistant Staphylococcus aureus (MRSA), is a critical global health threat.
  • Existing treatments are becoming less effective, necessitating the development of novel antibacterial agents.
  • Previous work identified a compound (c5) with moderate MRSA activity derived from an anticancer drug.

Purpose of the Study:

  • To design and synthesize novel cationic amphiphilic dioxonaphthoimidazolium bromides with enhanced lipophilicity.
  • To improve antibacterial activity against Gram-positive bacteria compared to the previous compound c5.
  • To evaluate the in vitro and in vivo efficacy and mechanism of action of the new compounds.

Main Methods:

  • Synthesis of novel N1,N3-dialkyldioxonaphthoimidazolium bromides with varied lipophilic side chains.
  • Determination of Minimum Inhibitory Concentrations (MICs) against Gram-positive bacteria, including MRSA.
  • Assessment of in vitro cytotoxicity and in vivo efficacy in a Drosophila melanogaster infection model.
  • Evaluation of reactive oxygen species (ROS) generation and bacterial resistance development.

Main Results:

  • Compound 11 (N1,N3-n-octylbenzyldioxonaphthoimidazolium bromide) displayed potent activity against MRSA and other Gram-positive bacteria (MICs: 0.19–0.39 μg/mL).
  • Compound 11 demonstrated superior in vivo efficacy compared to c5 and vancomycin in a Drosophila model of Staphylococcus aureus infection.
  • No bacterial resistance to compound 11 was observed after 16 passages, and it showed low toxicity in the Drosophila model despite in vitro cytotoxicity.

Conclusions:

  • Rational design of lipophilic, ROS-generating cationic amphiphiles can yield potent antibacterial agents.
  • Compound 11 represents a promising lead candidate for combating drug-resistant Gram-positive bacterial infections.
  • Optimized lipophilicity and ROS-generating pharmacophores are key strategies for developing new antibiotics.
Keywords:
AntibioticDrosophila melanogasterGram-positive bacteriaMethicillin-resistant Staphylococcus aureusN(1),N(3)-dialkyldioxonaphthoimidazolium bromide

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