Carmela Bonaccorso

New linezolid-like 1,2,4-oxadiazoles active against Gram-positive multiresistant pathogens.

The synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Replacement of the linezolid morpholine C-ring with 1,2,4-oxadiazole results in an antibacterial activity against Staphylococcus aureus both methicillin-susceptible and methicillin-resistant comparable or even superior to that of linezolid. While acetamidomethyl or thioacetoamidomethyl moieties in the C(5) side-chain are required, fluorination of the phenyl B ring exhibits a slight effect on an antibacterial activity but its presence seems to reduce the compounds cytotoxicity. Molecular modeling performed using two different approaches - FLAP and Amber software - shows that in the binding pose of the newly synthesized compounds as compared with the crystallographic pose of linezolid, the 1,2,4-oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring, since the H-bond interaction with U2585 is retained.

A gemini guest triggers the self-assembly of a calixarene capsule in water at neutral pH

A gemini guest having both aromatic units and negative charges induces the self-assembling of a homodimeric capsule when interacting with a positively charged calixarene at pH 7.

Guest-induced capsule formation based on concerted interactions in water at neutral pH

The interaction of a tetracationic calixarene (TAC4) with dianionic guest (BS) in water was studied with NMR, nano-ITC and ESI-MS experiments; the convergent evidence provided by these different techniques shows that the addition of a suitable guest molecule triggers the formation of a homodimeric capsule in aqueous neutral solution.

Modeling, design and synthesis of new heteroaryl ethylenes active against the MCF-7 breast cancer cell-line

A dataset of 50 compounds was used to generate a QSAR model and to design 9 new heteroaryl ethylenes. These compounds were synthesized, tested in vitro and a significant agreement with in silico predictions observed. Studies using Laser Scanning Confocal Microscopy pointed out that the compounds may act by different mechanisms.

Factors driving the self-assembly of water-soluble calix[4]arene and gemini guests: a combined solution, computational and solid-state study

Negatively charged gemini guests in the presence of a tetracationic host trigger the formation of self-assembling structures at physiological pH in water generating entities of the HG and H2G type (H = host and G = guest). ITC measurements show that the gemini guests are included via concerted electrostatic and hydrophobic interactions and that the formation of the HG adduct is enthalpically driven while the formation of the capsular entity (H2G) is driven by entropy gain. It is shown that the efficiency of capsule formation is influenced by the number of –CH2– units contained in the spacer and that spacers with an even number of methylene groups seem to be the best templating agents. In line with the above picture, MD simulations and DFT calculations show that the entropic contribution strongly depends on the length of the polymethylenic spacer. In the solid state, for the HG assembly three different structures are revealed by single crystal X-ray diffraction; the flexible interacting units create multiple interactions reaching the optimum balance between inter- and intramolecular energies. To the best of our knowledge, these are the first structures ever reported for water-soluble calixarenes and organic anions.

Hierarchical dependence of porphyrin self-aggregation: controlling and exploiting the complexity

Self-aggregation processes are rarely reproducible owing to their dependence on various experimental parameters (aging of stock solutions, their concentration, concentration of working solutions, ionic strength, etc.). However, by enucleating the dependence from one parameter (in this case, the dependence of aggregation from the concentration of the working solutions), it has been possible to hierarchically control self-aggregation of the protonated form of tetrakis-(4-sulfonatophenyl)-porphyrin.

Photochemistry and DNA-affinity of some pyrimidine-substituted styryl-azinium iodides

The relaxation properties of the excited states of three iodides of trans-1,2-diarylethene analogues (where one aryl group is a methylpyridinium, methylquinolinium or dimethylimidazolium group and the other one is a phenyl ring para-substituted by a pyrimidine ring) have been investigated in buffered (pH = 7) aqueous solution. As found in previous works for several analogues, these quaternized salts undergo efficient trans→cis photoisomerization while the yield of the radiative deactivation is very small at room temperature. The solvent effect on the spectral behaviour indicates the occurrence of intramolecular charge transfer which can induce interesting non-linear optical properties. The results of a study of the interactions of these salts with DNA, which might affect the cell metabolism, showed a relatively modest binding affinity for the pyridinium and imidazolium salts and a more substantial affinity for the quinolinium analogue. The formation of ligand-DNA complexes affects only slightly the radiative relaxation yield while leading to a relevant reduction of the isomerization yield. Measurements of the linear dichroism behaviour of the three compounds and comparison with three analogues bearing furan or thienyl groups, which have been found to display different affinity with DNA in previous works, gave interesting information on the nature of the ligand-DNA binding of these compounds.

Stereochemistry and thermodynamics of the inclusion of aliphatic and aromatic anionic guests in a tetracationic calix[4]arene in acidic and neutral aqueous solutions

A cationic calix[4]arene derivative binds both aliphatic and aromatic anions in aqueous solution thanks to concerted electrostatic and hydrophobic interactions. 1H NMR and potentiometric data show that the host flexibility changes as a function of pH. 1H NMR and isothermal titration calorimetry (ITC) studies, also supported by ESI-MS data, show that inclusion yields supramolecular complexes of the guest⊂host type only. Binding becomes weaker as the pH increases due to rigidification of the host in neutral aqueous solutions, and is enthalpically favoured for all the supramolecular complexes, regardless of pH.

New potent antibacterials against Gram-positive multiresistant pathogens: effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles.

The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The adopted strategy involved a molecular modelling approach, the synthesis and biological evaluation of new designed compounds, enantiomers separation and absolute configuration assignment. Experimental determination of the antibacterial activity of the designed (S)-1-((3-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea and (S)-1-((3-(3-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea against multidrug resistant linezolid bacterial strains was higher than that of linezolid.

Gemini guests with spacers of various length drive the self-assembling of supramolecular capsules in water at neutral pH differently

Water-soluble homodimeric capsules resulting from the electrostatic and hydrophobic interactions between a tetracationic calixarene receptor and gemini guests having the negatively charged ends separated by a (–CH2–)n (n = 2–6) spacer are reported. The formation of the supramolecular capsules occurs through concerted hydrophobic and electrostatic interactions between the charged and aromatic groups of the guests and the host as indicated by 1H NMR and DOSY NMR data. The different size of the guests may strongly affect the stability of the capsule. The surprising features of these host–guest systems disclose new paths for the design of more efficient anion-templated capsules in highly competitive media such as water.