1. Academic Validation
  2. Design, synthesis and antibacterial evaluation of low toxicity amphiphilic-cephalosporin derivatives

Design, synthesis and antibacterial evaluation of low toxicity amphiphilic-cephalosporin derivatives

  • Eur J Med Chem. 2024 Mar 15:268:116293. doi: 10.1016/j.ejmech.2024.116293.
Shengcong Chen 1 Shangshang Qin 1 Ruirui Li 1 Ye Qu 1 Maxwell Ampomah-Wireko 1 Lauraine Nininahazwe 1 Meng Wang 1 Chen Gao 1 En Zhang 2
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, PR China.
  • 2 School of Pharmaceutical Sciences, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, PR China; Pingyuan Laboratory (Zhengzhou University), PR China. Electronic address: zhangen@zzu.edu.cn.
Abstract

Global public health is facing a serious problem as a result of the rise in Antibiotic resistance and the decline in the discovery of new Antibiotics. In this study, two series of amphiphilic-cephalosporins were designed and synthesized, several of which showed good Antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships indicated that the length of the hydrophobic alkyl chain significantly affects the Antibacterial activity against Gram-negative bacteria. The best compound 2d showed high activity against drug-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) with MICs of 0.5 and 2-4 μg/mL, respectively. Furthermore, 2d remained active in complex mammalian body fluids and had a longer post-antibiotic effect (PAE) than vancomycin. Mechanism studies indicated that compound 2d lacks membrane-damaging properties and can target penicillin-binding proteins to disrupt Bacterial cell wall structure, inhibit the metabolic activity and induce the accumulation of Reactive Oxygen Species (ROS) in bacteria. Compound 2d showed minimal drug resistance and was nontoxic to HUVEC and HBZY-1 cells with CC50 > 128 μg/mL. These findings suggest that 2d is a promising drug candidate for treating Bacterial infections.

Keywords

Amphiphilic compound; Antibacterial activity; Antimicrobial peptides mimics; Cephalosporin; Low-toxicity; Pyridine quaternary ammonium.

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