Universitatea Alexandru Ioan Cuza din Iasi


The synthesis of new hybrid [2.2]paracyclophane-flavonoids systems with potential antimicrobial activity

Petru Poni






Project title: The synthesis of new hybrid [2.2]paracyclophane-flavonoids systems with potential antimicrobial activity

Project code: PN-III-P1-1.1-PD-2016-0962

Financed by: UEFISCDI - Romanian National Budget

Expected results:

The synthesis and testing of novel 1,3-dithiolium antibacterial agents and the publication of a paper in an international ISI ranked journal.


A major problem in our modern-day society, especially in the medicine field, is represented by drug-resistant microbes, which are resistant to a more and more broad spectrum of antibiotics. This issue is due to the extensive, sometimes negligent use of antibiotics in human treatment and agriculture. Not only beta-lactams, but also other groups of antibiotics, such as quinolones and macrolides, prove to be ineffective in certain cases. Therefore, the synthesis of new and more active antibiotics, preferably based on new molecular scaffolds, are needed. In this context, flavonoids represent potentially good candidates for such antimicrobial agents. Flavonoids are a class of polyphenolic compounds that act as secondary metabolites in plants and possess a C6-C3-C6 backbone. Presently, more than 9000 flavonoids are known, with this number increasing every year. The great interest for this class of compounds derives from the wide display of biological activities, which are in a strong relationship with the structure of the flavonoids. It is to be mentioned that for centuries, mixtures that contain flavonoids have been used in traditional medicine for treatment and prevention of various infectious and toxin-mediated diseases, such as wound infections, acne, respiratory infection, gastrointestinal disease and urinary tract infections. For example, the healing properties of propolis are known since Hippocrates time (460ľ377 BC) and this balm was prescribed for the treatment of sores and ulcers. The antimicrobial properties of propolis have been attributed to its high flavonoid content and in particular the presence of the flavonoids galangin and pinocembrin. Various studies have reported that these compounds possess many biological properties, including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory and even cytotoxic antitumor activities. An important and rich source of anti-infective agents is represented by natural products. Even so, in recent years researchers have shown interest in semisynthetic and synthetic flavonoids, some of these compounds being more active than the natural flavonoids.

Thus, following the interest in synthetic flavonoids, recently our research group reported the antibacterial activity of a series of tricyclic flavonoids containing a 1,3-dithiolium ring. One of the tested flavonoids was found to have a minimum inhibitory concentration of 0,48 micrograms/mL for Staphylococcus aureus and 3,9 micrograms/mL for Escherichia coli. More than that, it was found that this kind of compounds exhibit good to excellent antibacterial activities against both Gram-positive and Gram-negative bacteria. Other studies revealed that the tricyclic flavonoids developed in our laboratory are inhibiting and also killing bacterial cells at very low concentrations. Given the promising results obtained so far and based on our experience in this field, we consider that these tricyclic flavonoids are good candidates for designing new and highly efficient antimicrobial agents that deserve to be investigated further.

The other class of compounds, that we are trying to merge with the flavonoid framework, is represented by [2.2]paracyclophanes. Cyclophanes are strained organic molecules which contain aromatic ring(s) as well as aliphatic unit(s). The aromatic rings provide rigidity to their structure, whereas the aliphatic unit(s) forms bridge(s) between the aromatic rings and also provide flexibility to the overall structure. [2.2]Paracyclophanes ([2.2]PC) are a class of organic compounds which have drawn attention ever since their first appearance in the literature. The molecules of these compounds are madeľup of two benzene rings placed one on top of the other, bound together by ethylene bridges in their para positions. The cyclophane chemistry is a fast developing field, as proven by a recent publication by Gleiter and Hopf, which describes the applications of cyclophanes in stereoselective synthesis and the incorporation of cyclophanes in complex molecular structures, like heterocycles and polymers. Initially, [2.2]paracyclophane and its derivatives were studied because of their special geometry, sterical properties, transannular interactions and cycle tension. Because of the rigid molecular frame, recent research suggests using the electronical properties of these compounds in the synthesis of polymers and charge-transfer complexes. A number of cyclophanes have been designed and developed over the years for the selective recognition of various guest biomolecules. These biomolecules include nucleosides and nucleotides, amino acids, proteins and various nucleic acid structures. These cyclic systems are capable of encapsulating and stabilizing guest molecules in the hydrophobic cavity through various non-covalent interactions. In this context, understanding the interactions of functional cyclophanes with various biomolecules is important, due to the favorable properties inherently exhibited by these macrocyclic systems. The cyclophane skeleton is a core structural unit in many biologically active natural products such as macrocidin A and B, nostocyclyne A, and in the turriane family of natural products. Macrocidin A and macrocidin B belong to a family of plant pathogens produced by Phoma macrostoma, a microorganism parasitic to Canadian thistle. Macrocidins contain a tetramic acid group in their skeleton and show selective herbicidal activity on broadleaf weeds but do not affect grasses. Nostocyclyne A is an acetylenic cyclophane derivative isolated from a terrestrial Nostoc species, with antimicrobial activity. The turriane family of natural products of type was isolated from the stem wood of the Australian tree Grevillea striata. Turrianes are effective DNA-cleaving agents in the presence of Cu(II).

Cyclophanes are also used in research areas such as pharmaceuticals, catalysis and supramolecular chemistry. Also, in the past few years a new family of paracyclophanes, called pillar[5]arene was developed, that exhibit an unique column-like structure, which could be used to build artificial transmembrane channels.

The 2007 European Antimicrobial Resistance Surveillance System (EARSS) Report, disclosed relevant and worrying statistics for Romania by comparison with other EU countries. According to this study, Romanian data on antimicrobial resistance show high levels, more than 25%, a constantly increasing trend in the past years. Therefore, there is a pressing need worldwide to develop new therapeutic agents, ideally in the form of new classes of antibacterial agents as the structural modification of drugs to which resistance has already been developed rarely provides a major solution.

Based on the encouraging results mentioned before, along with the accumulated experience in both flavonoids and [2.2]paracyclophanes, we consider to have a strong background in launching and developing new strategies for the synthesis of novel compounds with potential antimicrobial activity.


The main target of the present project is to synthesize new hybrid [2.2]paracyclophane-flavonoids systems with potential antimicrobial activity. The introduction of one or more tricyclic flavonoids moieties into the [2.2]paracyclophane framework is worth investigating, as the new derivatives might display enhanced antimicrobial activity. Moreover, these new molecules could also possess other biological properties. In order to achieve the main goal, several objectives must be addressed in correlation with the outcome of the project:

1. The synthesis of 1,3-dithiolium flavonoids linked to a [2.2]paracyclophane core and evaluation of their structural stability.

2. Evaluation of the antibacterial spectrum of the synthesized flavonoids.

3. Structure-activity relationship for antibacterial activity of the synthesized flavonoids.

4. Dissemination of the project results.