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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. 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.
Subsequently, very good results appeared, for example, for peptidocalix[4]arenes (Figure 4) with good activity against MRSA (methicillin-resistant S. aureus) (4 to 8 µg/mL) [57][58][59]. From 2006, calix[4]arene positively charged by the introduction of guanidinium functions showed excellent activities on reference bacterial strains (Figure 4). These last introduced on the upper rim displays a significant antibacterial activity (MIC <8 µg/mL) against the bacterial reference strains E. coli, S. aureus, E. faecalis and P. aeruginosa [18][60], but also on the clinical isolates penicillinase producing E. coli, methicillin-resistant S. aureus, vancomycin-resistant E. faecium, vancomycin- and teicoplanin-resistant E. faecalis, and P. aeruginosa overexpressing efflux pumps [61]. This guanidinium calixarene and its derivatives also have very good activity against a particular strain: Mycobacterium tuberculosis [60][62].
Another examples concern a water-soluble macromolecule based on calix[4]arene and morpholine units [63], appears to have an excellent activity profile with the inhibitions of growth were measured at 4 µg/mL against gram-positive and gram-negative species, but also a serie of azo compounds [64] showing very good activities through CMI measurements on five Gram-positive bacterial strains (B. subtilis, S. aureus, methicillin-resistant S. aureus (MRSA), S. epidermidis, and E. faecalis) (<10 µg/mL).
Finally, a recent study confirms the interest of calixarenes carrying cationic functions but also of the impact of conformation [65] (Figure 4) as described in a previous study [60]. Indeed, the ammonium derivatives concerned exhibit activities close to 1 µg/ml against Gram-positive and Gram-negative strains.
These studies propose, for example, the introduction of penicillin via amide or ester functions, which should release the biologically active free acid and amine after hydrolysis by esterases [66][67] (Figure 5). The same strategy allows the synthesis of bis-quinolone derivatives [68][69] and a study of the anti-bacterial activity against Gram-positive reference ATCC strains, S. aureus and E. faecalis, as well as against two Gram-negative reference strains E. coli and P. aeruginosa. Designed as hydrophobic compounds, these structures are not really easy for in vitro standard evaluation as antimicrobial agents. Thus, an additional study proposes the development of water-soluble compounds via the introduction of ammonium functions [70]. Other researchers have also obtained promising results through the synthesis and biological evaluation of penicillins V and X clustered by a calixarene scaffold [71] and the corresponding cephalosporine derivatives [72] (Figure 5). The impact of cyclotetramerization was demonstrated by a notable increase in activity on all penicillin cyclotetramer strains versus monomers.
Figure 5. Examples of molecular carriers/drug delivery: penicillin (left) or cephalosporine (right)
In this sense, researchers have developed complex structures of mononuclear copper [73][74] (Figure 6) for their antibacterial activities against Gram-positive (B. subtilis, B. cereus, E. faecalis (clinic sample), S. aureus) and Gram-negative bacteria (E. coli, E. coli, P. aeruginosa, Proteus vulgaris) or binuclear [75] (Figure 6) active against Gram-positive S. albus and Gram-negative E. coli. On the other hand, the thiosemicarbazide moieties and their thiosemicarbazone derivatives known for their ability to coordinate with transition metals by bonding with sulfur and nitrogen atoms [167,168] allowed the development of cobalt (II), nickel (II), copper (II), or zinc (II) complexes.
Figure 6. Examples of mononuclear copper (left) and binuclear copper (right) complexes