Membrane-Active Antibacterial Agents Based on Calix[4]arene Derivatives: Synthesis and Biological Evaluation.

Shanfang Fang,Shouping Liu,Jiayong Liu,Shuimu Lin,Rongcui Zhong,Yongzhi Chen,Haizhou Li,Yuan-Ye Dang,Hongxia Li

doi:10.3389/fchem.2022.816741

Abstract

Bacteria have developed increasing resistance to currently used antimicrobial agents. New classes of antimicrobial drugs are urgently required to fight drug-resistant pathogens. Here, we designed and synthesized a series of calix[4]arene derivatives as antibacterial agents by biomimicking the structural properties and biological functions of antibacterial peptides. After introducing cationic hydrophilic moieties and preliminary structural optimization, we obtained a lead compound (16) that exhibited excellent antibacterial activity against Gram-positive bacteria, low toxicity toward mammalian cells and poor hemolytic activity. The antibacterial mechanism studies showed that compound 16 can destroy bacterial cell membrane directly, leading to bacterial death and a low tendency to develop bacterial resistance.

Highlights

The development of multi-drug resistant bacteria and the decrease in the discovery of new antibiotics pose a major threat to public health in the 21st century (Lyddiard et al, 2016; Woolhouse et al, 2016; Monserrat-Martinez et al, 2019)
We initially planned to design and synthesize a four-arm modified intermediate epoxy compound 2a (Scheme 3), and 2a reacted with the corresponding amines to prepare a series of amphiphilic cationic four-arm modified calixarene derivatives as antibacterial compounds (Scheme 3)
The anti-Gram-positive bacterial activities of these compounds are determined by the hydrophobic side chains connected to positive charge centers. These results suggested that the secondary amine substituents with short hydrophobic side chains can greatly improve the antibacterial activity of calix[4]arene derivatives, and slightly increase the hemolytic activity of calix[4]arene derivatives

Summary

Introduction

The development of multi-drug resistant bacteria and the decrease in the discovery of new antibiotics pose a major threat to public health in the 21st century (Lyddiard et al, 2016; Woolhouse et al, 2016; Monserrat-Martinez et al, 2019). Due to the rapid development of antimicrobial resistance, short medication cycle, and low profits of antimicrobial agents, many pharmaceutical companies have greatly reduced their investment in the development of antimicrobial agents, which could slow the discovery of new antibiotics (Livermore, 2011; Rogers et al, 2012). Most newly approved antibiotics are likely to develop rapid resistance as most of them belong to known classes of antibiotics, based on the molecular scaffolds of traditional antibiotics (Molchanova et al, 2017). If effective measures are not taken to combat antibiotic resistance, we will return to the “pre-antibiotic era,” and most surgical procedures will not be safe to implement

Methods

Results

Conclusion