Abstract
The rapid growth of serious infections caused by antibiotic resistant bacteria, especially the nosocomial ESKAPE pathogens, has been acknowledged by Governments and scientists and is one of the world’s major health problems. Various strategies have been and are currently investigated and developed to reduce and/or delay the bacterial resistance. One of these strategies regards the design and development of antimicrobial hybrids and conjugates. This unprecedented critical review, in which our continuing interest in the synthesis and evaluation of the bioactivity of imidazole derivatives is testified, aims to summarise and comment on the results obtained from the end of the 1900s until February 2020 in studies conducted by numerous international research groups on the synthesis and evaluation of the antibacterial properties of imidazole-based molecular hybrids and conjugates in which the pharmacophoric constituents of these compounds are directly covalently linked or connected through a linker or spacer. In this review, significant attention was paid to summarise the strategies used to overcome the antibiotic resistance of pathogens whose infections are difficult to treat with conventional antibiotics. However, it does not include literature data on the synthesis and evaluation of the bioactivity of hybrids and conjugates in which an imidazole moiety is fused with a carbo- or heterocyclic subunit.
Highlights
Serious infections caused by antibiotic resistant bacteria, especially the six nosocomial ESKAPE pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp., are one of the world’s major healthcare problems in the 21st century and are a cause of morbidity and mortality [1]
The review, in which significant attention was paid to summarise the strategies used to overcome the antibiotic resistance of pathogens whose infections are difficult to treat with conventional antibiotics, was organised in the following main sections: (i) heterocyclic conjugates and hybrids bearing nitroimidazole moiety; (ii) coumarin/imidazole hybrids and conjugates; (iii) furanchalcone/imidazole hybrids; (iv) hybrids based on benzofuran, quinazolinone, and imidazolium moieties; (v) 1H-imidazoles containing azetidinone derivatives; (vi) pyrrole/imidazole and indole/imidazole hybrids; (vii) pyrazole/imidazole hybrids; (viii) 1,2,3-triazole/imidazole hybrids and conjugates; (ix) hybrids of imidazole derivatives and 5-membered heterocycles containing oxygen and nitrogen; (x) 1,8-naphthalimide/imidazole hybrids; (xi) bis-imidazoles; (xii) pyridine/imidazole hybrids; (xiii) quinoline/imidazole hybrids; (xiv) pyrimidine/imidazole hybrids; (xv) addendum
These compounds, which were separated by flash chromatography, were tested for their antibacterial activity against bacterial species including P. aeruginosa, E. coli, S. aureus, and Clostridium sporogenes, a Gram-positive anaerobic bacterium, and it was found that many of them had not detectable activity at concentration as high as 0.5 mg/cm3
Summary
Serious infections caused by antibiotic resistant bacteria, especially the six nosocomial ESKAPE pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp., are one of the world’s major healthcare problems in the 21st century and are a cause of morbidity and mortality [1]. Overconsumption and misuse of antibiotics and exposure to infections in hospitals has caused the emergence of multi-drug resistant bacteria many of which, according to the World Health Organization (WHO) list, are Gram-negative pathogens [2] Their structure consists of a protective extra outer membrane that antibiotics have great difficulty going through. In some recent papers, this classification of antibacterial agents in hybrids and conjugates has not been followed and the antibacterial substances in which a single pharmacophore is connected to a non-bacterial subunit through a spacer or linker have been named both as antibacterial hybrids and conjugates In this unprecedented critical review we have defined an antibiotic hybrid as a synthetic combination of two or more covalently linked pharmacophores belonging to an established agent known to elicit an antibacterial effect. Whenever possible, MIC and (sometimes) IC50 values have been reported on a molar basis, regardless of the data format in the original papers
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