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Since the discovery of polyphenolic resins 150 years ago, the study of polymeric compounds named calix[ n ]arene has continued to progress, and those skilled in the art perfectly know now how to modulate this phenolic ring. Consequently, calix[ n ]arenes are now used in a large range of applications and notably in therapeutic fields. In particular, the calix[4]arene exhibits multiple possibilities for regioselective polyfunctionalization on both of its rims and offers researchers the possibility of precisely tuning the geometry of their structures. Thus, in the crucial research of new antibacterial active ingredients, the design of calixarenes finds its place perfectly. This review provides an overview of the work carried out in this aim towards the development of intrinsically active prodrogues or metallic calixarene complexes. Out of all the work of the community, there are some excellent activities emerging that could potentially place these original structures in a very good position for the development of new active ingredients.

A new family of poly-guanidinium species with a benzene core as the organising agent has been developed. Their antibacterial properties have been evaluated against reference Gram positive and Gram negative bacteria, and their cytotoxicity against eukaryotic cells. Most of these compounds exhibited Minimum Inhibitory Concentrations in the micromolar range., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Two well-known antibiotic heterocycles, the 'quinolone' nalidixic acid and the β-lactam penicillin V, active at different levels of the bacterial growth process, have been attached via an ether-ester junction to the p-tert-butylcalix[4]arene lower rim, in alternate position. The resulting hydrophobic molecular drug-organisers were fully characterized, and evaluated over two Gram negative and three Gram positive reference strains, using disk diffusion assays with disks impregnated with solution of title compound in pure DMSO. An interesting activity was observed over Staphylococcus aureus ATCC 25923 with the dis-symmetrical podand incorporating one penicillin and one nalidixic ester moieties., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The tetra-para-guanidinoethyl-calix[4]arene, its distally-disubstituted ether derivatives involving 2,2'-bithiazolyl- or 2,2'-bipyridyl-methyl groups, as well as the para-guanidinoethylphenol and its analogous derivatives have been synthesized, fully characterized and evaluated as antibacterial agents towards both gram positive and gram negative reference bacteria. The simple phenolic species showed lower activity than their calixarene analogues, confirming the hypothesis that a synergistic effect should result from the spatial organization of guanidinium and heterocycles on a macrocyclic scaffold. Introduction of the bithiazole and bipyridine substituents enhanced the activity of simple phenol derivatives, reaching, for the two Staphylococcus aureus strains in particular, the values obtained for their calixarenic parents. MTT viability assays were carried out to determine selectivity indexes.

A water-soluble calixarene-based heterocyclic podand incorporating a quinolone antibiotic subunit, the nalidixic acid, was synthesised and fully characterised. Its prodrug behaviour was assessed in vitro by HPLC, demonstrating the release of the tethered quinolone in model biological conditions. Microbiological studies performed on various Gram-positive and Gram-negative reference strains showed very interesting antibacterial activities.

Objectives: Emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. In this study, the in vitro antibacterial activity of para-guanidinoethylcalix[4]arene was evaluated and compared with that of its constitutive monomer, para-guanidinoethylphenol. Hexamidine, a widely used antiseptic, and synthalin A, an old antidiabetic and anti-trypanosomal compound, were chosen as references., Methods: MIC and MBC were determined for five reference strains (Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and ATCC 29213, Enterococcus faecalis ATCC 29212 and Pseudomonas aeruginosa ATCC 27853), as well as five antibiotic-resistant clinical isolates. Toxicity on MRC-5 and HaCaT eukaryotic cell lines was also evaluated by MTT and Neutral Red assays., Results: No antibacterial activity was observed for para-guanidinoethylphenol (MIC >or= 512 mg/L) and synthalin A (MIC >or= 64 mg/L). Conversely, para-guanidinoethylcalix[4]arene and hexamidine: (i) showed a broad antibacterial spectrum, both on Gram-positive and on Gram-negative bacteria (MIC = 4 mg/L against E. coli and 8 mg/L against S. aureus for para-guanidinoethylcalix[4]arene), to a lesser degree against E. faecalis and P. aeruginosa (MIC = 32 mg/L); (ii) were bacteriostatic (MBC >or= 256 mg/L); and (iii) MICs and MBCs obtained for clinical isolates were similar to those obtained with reference strains. Both compounds, the monomer and the calixarene, showed no apparent cytotoxicity, whereas hexamidine and synthalin A had significant toxic effects that increased with time and concentration and in a range of 100-1000 times that for calixarene., Conclusions: In conclusion, results confirm para-guanidinoethylcalix[4]arene as a broad-spectrum new agent or an auxiliary in antimicrobial chemotherapy.

The antibacterial activities of the para-guanidinoethylphenol and of its cyclic tetramer, the tetra-para-guanidinoethyl-calix[4]arene, have been evaluated on reference gram-positive and gram-negative bacteria. Antibiotic disk diffusion assays completed by micromethod technique were employed to determine if a synergistic effect could be expected from the spatial organisation of the monomer into its cyclic tetrameric analogue. Disk diffusion assays and microdilution experiments revealed better properties for the calixarene species, with a real and important gain of activity with regards to the monomer.