Under the Influence of Water: Molecular Recognition of Organic Hydrophilic Molecules in Water with a Prismarene Host Driven by Hydration Effects.

A water-soluble prism[5]arene host can form endo-cavity complexes with hydrophilic organic substances in water by displacing frustrated water molecules from its deep cavity. Water molecules structured at both rims of the prismarene host can mediate hydrogen bonding interactions with the guest. Water-mediated hydrogen bonding interactions were invoked here to elucidate the elevated binding affinities and selectivity of the prismarene host toward hydrophilic organic guests. We show that water at the interface of a host-guest complex can act as an extension of the host structure, facilitating the accommodation of neutral guests within the binding site. This study highlights the crucial role of water in facilitating supramolecular interactions between a deep-cavity prismarene host and organic hydrophilic guests in aqueous medium.

The Resorcinarene Hexameric Capsule as a Supramolecular Photoacid to Trigger Olefin Hydroarylation in Confined Space.

The self-assembled resorcinarene capsule C6 shows remarkable photoacidity upon light irradiation, which is here exploited to catalyze olefin hydroarylation reactions in confined space. An experimental pKa* value range of -3.3--2.8 was estimated for the photo-excited hexameric capsule C6*, and consequently an increase in acidity of 8.8 log units was observed with respect to its ground state (pKa=5.5-6.0). This makes the hexameric capsule the first example of a self-assembled supramolecular photoacid. The photoacid C6* can catalyze hydroarylation reaction of olefins with aromatic substrates inside its cavity, while no reaction occurred between them in the absence of irradiation and/or capsule. DFT calculations corroborated a mechanism in which the photoacidity of C6* plays a crucial role in the protonation step of the aromatic substrate. A further proton transfer to olefin with a concomitant C-C bond formation and a final deprotonation step lead to product releasing.

Insights into the Friedel-Crafts Benzoylation of N-Methylpyrrole inside the Confined Space of the Self-Assembled Resorcinarene Capsule.

Friedel-Crafts benzoylation of N-methylpyrrole 2 can run inside the confined space of the hexameric resorcinarene capsule C. The bridged water molecules at the corner of C act as H-bonding donor groups to polarize the C-Cl bond of benzoyl chlorides 3a-f. Confinement effects on the regiochemistry of the FC benzoylation of N-methylpyrrole are observed. The nature of the para-substituents of 3a-f and their ability to establish H-bonds with the water molecules of C work synergistically with the steric constrictions imposed by the capsule to drive the regiochemistry of products 4a-f. QM investigations indicate that inside the cavity of C, the FC benzoylation of 2 has a bimolecular concerted SN2 mechanism, appropriately, above-plane nucleophilic vinylic substitution (SNVπ)─supported by H-bonding interactions between water molecules and both the leaving Cl atom and the carbonyl group.

Hexahexyloxycalix[6]arene, a Conformationally Adaptive Host for the Complexation of Linear and Branched Alkylammonium Guests.

Hexahexyloxycalix[6]arene 2b leads to the endo-cavity complexation of linear and branched alkylammonium guests showing a conformational adaptive behavior in CDCl3 solution. Linear n-pentylammonium guest 6a+ induces the cone conformation of 2b at the expense of the 1,2,3-alternate, which is the most abundant conformer of 2b in the absence of a guest. In a different way, branched alkylammonium guests, such as tert-butylammonium 6b+ and isopropylammonium 6c+, select the 1,2,3-alternate as the favored 2b conformation (6b+/6c+⊂2b1,2,3-alt), but other complexes in which 2b adopts different conformations, namely, 6b+/6c+⊂2bcone, 6b+/6c+⊂2bpaco, and 6b+/6c+⊂2b1,2-alt, have also been revealed. Binding constant values determined via NMR experiments indicated that the 1,2,3-alternate was the best-fitting 2b conformation for the complexation of branched alkylammonium guests, followed by cone > paco > 1,2-alt. Our NCI and NBO calculations suggest that the H-bonding interactions (+N-H···O) between the ammonium group of the guest and the oxygen atoms of calixarene 2b are the main determinants of the stability order of the four complexes. These interactions are weakened by increasing the guest steric encumbrance, thus leading to a lower binding affinity. Two stabilizing H-bonds are possible with the 1,2,3-alt- and cone-2b conformations, whereas only one H-bond is possible with the other paco- and 1,2-alt-2b stereoisomers.

Characterization of Linezolid-Analogue L3-Resistance Mutation in Staphylococcus aureus.

In a previous study, a linezolid analogue, called 10f, was synthesized. The 10f molecule has an antimicrobial activity comparable to that of the parental compound. In this study, we isolated a Staphylococcus aureus (S. aureus) strain resistant to 10f. After sequencing the 23S rRNA and the ribosomal proteins L3 (rplC) and L4 (rplD) genes, we found that the resistant phenotype was associated with a single mutation G359U in rplC bearing to the missense mutation G120V in the L3 protein. The identified mutation is far from the peptidyl transferase center, the oxazolidinone antibiotics binding site, thus suggesting that we identified a new and interesting example of a long-range effect in the ribosome structure.

Carbocation catalysis in confined space: activation of trityl chloride inside the hexameric resorcinarene capsule.

Carbocation catalysis can be performed inside the confined space of the hexameric resorcinarene capsule. The inner cavity of the capsule can host the trityl carbocation, which catalyses the Diels-Alder reaction between dienes and unsaturated aldehydes. Experimental results and in silico calculations show that the hexameric resorcinarene capsule C6 can promote the formation of the trityl carbocation from trityl chloride through the cleavage of the carbon-halogen bond promoted by OH⋯X- hydrogen bonding. Here it is shown that the combination of the nanoconfined space and the latent carbocation catalysis provides a convenient complementary strategy for the typical carbocation catalysis. The latent strategy bypasses the typical pitfalls associated with active carbocations and provides control of the reaction efficiency in terms of reaction rate, conversion, and selectivity.

Acquired methemoglobinemia in children presenting to Italian pediatric emergency departments: a multicenter report.

INTRODUCTION: Methemoglobinemia (MetHb) is a rare inherited or acquired cause of cyanosis in children. Owing to its rarity, case reports and case series are mostly available in the current literature. This study reports data on a large sample of children with acquired MetHb. METHODS: Data on patients admitted for acquired MetHb between January 2007 to December 2020 was extracted from the databases of five Italian pediatric emergency departments (EDs). Demographical and clinical characteristics was reported and discussed. RESULTS: Nineteen cases of acquired MetHb were evaluated. Ten patients (52.6%) were male and 9 (47.4%) were female. The median age was 8.23 months. The median time from trigger to symptom onset was 6 hours. Mostly, the intoxication presumptively occurred by home ingestion of contaminated food, mainly badly preserved vegetable broth. All patients were cyanotic at admission, most patients also presented tachycardia and/or tachypnea, and two patients were comatose. Antidotal therapy with methylene blue was given in 14 patients (73.7%). The median hospital stay was 2 days. All patients survived. DISCUSSION: As MetHb leads to the pathognomonic brown blood discoloration, blood gas analysis is mandatory immediately upon hospital arrival of a cyanotic patient. A correct medical history is crucial to identify the trigger and remove it. In our sample, the age onset was much lower than in the previous literature, and MetHb mainly due to ingestion of contaminated vegetable broth. Methylene blue led to a rapid recovery in all patients. Oxygen therapy may well lead to complete recovery when methemoglobin levels do not exceed 30% in asymptomatic and 20% in mildly symptomatic patients. CONCLUSIONS: The diagnosis and management of acquired MetHb in the emergency setting requires acknowledgment of this condition as a cause of cyanosis in the weaning child. Indeed, when promptly recognized and treated, this severe condition rapidly resolves with no significant acute sequelae.

Molecular Recognition in an Aqueous Medium Using Water-Soluble Prismarene Hosts.

The synthesis of water-soluble prism[n]arenes (n = 5 and 6) bearing anionic carboxylato groups on the rims is described. The binding properties of this novel class of water-soluble hosts are studied by nuclear magnetic resonance and calorimetry. The complexation of singly and doubly charged ammonium guests with the more rigid pentamer is enthalpically driven by secondary interactions, while the thermodynamic fingerprint for the larger hexamer reveals driving forces that strongly depend on the guest charge and/or size.

Unusual Calixarenes Incorporating Chromene and Benzofuran Moieties Obtained via Propargyl Claisen Rearrangement.

Monopropargyloxy-tripropoxy-calix[4]arene 1 was subjected to a propargyl Claisen rearrangement to give unusual calix[3]arene[1]chromene and homocalix[3]arene[1]benzofuran macrocycles. Quantum mechanical density functional theory calculations indicated that an initial [3,3] sigmatropic reaction affords a highly reactive allene intermediate, stabilized by two main diradical pathways leading to six- and five-membered oxygenated rings. In the presence of a n-butylammonium guest, calix[3]arene[1]chromane 6 forms two stereoisomeric complexes stabilized by +N-H···O and cation···π interactions.

Expanding Coefficient: A Parameter To Assess the Stability of Induced-Fit Complexes.

Here we propose a new parameter, the Expanding Coefficient (EC), that can be correlated with the thermodynamic stability of supramolecular complexes governed by weak secondary interactions and obeying the induced-fit model. The EC values show a good linear relationship with the log Kapp of the respective pseudorotaxane complexes investigated. According to Cram's Principle of Preorganization, the EC can be considered an approximate mechanical measure of the host's reorganization energy cost upon adopting the final bound geometry.

The Odd Couple(s): An Overview of Beta-Lactam Antibiotics Bearing More Than One Pharmacophoric Group.

ß-lactam antibiotics are among the most important and widely used antimicrobials worldwide and are comprised of a large family of compounds, obtained by chemical modifications of the common scaffolds. Usually these modifications include the addition of active groups, but less frequently, molecules were synthesized in which either two ß-lactam rings were joined to create a single bifunctional compound, or the azetidinone ring was joined to another antibiotic scaffold or another molecule with a different activity, in order to create a molecule bearing two different pharmacophoric functions. In this review, we report some examples of these derivatives, highlighting their biological properties and discussing how this strategy can lead to the development of innovative antibiotics that can represent either novel weapons against the rampant increase of antimicrobial resistance, or molecules with a broader spectrum of action.

Kinetic and Thermodynamic Modulation of Dynamic Imine Libraries Driven by the Hexameric Resorcinarene Capsule.

The composition of dynamic covalent imine libraries (DCL) adapts to the presence of the hexameric resorcinarene capsule. In the presence of the self-assembled capsule, a kinetic and thermodynamic modulation of the imine constituents of the DCLs was observed, which was induced by an unusual predatory action of the capsule on specific imine constituents. More complex 2 × 2 DCLs also adapt to the presence of the hexameric capsule, showing a thermodynamic and kinetic modulation of the constituents induced by the predatory action of the capsule. By cross-referencing experimental data, a good selectivity (up to 66%) for one constituent can be induced in a 2 × 2 DCL.

An Atom-Economical Method for the Formation of Amidopyrroles Exploiting the Self-Assembled Resorcinarene Capsule.

Here is reported the first example of an organocatalyzed coupling between pyrrole and isocyanates in a nanoconfined space. The hexameric resorcinarene capsule C is able to catalyze the direct coupling between isocyanates and pyrroles to give amidopyrroles with excellent yields and selectivities. The reaction catalyzed by C prevents the use of expensive and poorly atom-economical reagents. As in natural enzymes, the cavity of C is able to discriminate between isomeric substrates.

New compounds for a good old class: Synthesis of two Β-lactam bearing cephalosporins and their evaluation with a multidisciplinary approach.

Antimicrobial resistance is spreading massively in the world and is becoming one of the main health threats of the 21st century. One of the possible strategies to overcome this problem is to modify the known classes of antibiotics in a rational way, with the aim of tuning their efficacy. In this paper, we present the synthesis and the evaluation of the biological activity of a series of two ß-lactam bearing cephalosporin derivatives, in which an additional isolated azetidinone ring, bearing different substituents, is joined to the classical cephalosporanic nucleus by a chain of variable length. A computational approach has been also applied in order to predict the molecular interactions between some representative derivatives and selected penicillin-binding proteins, the natural targets of ß-lactam antibiotics. All these derivatives are active against Gram-positive bacteria, with MIC100 comparable or even better than that of the reference antibiotic ceftriaxone, and show no or very low cytotoxic activity on different cell lines. Overall, these molecules appear to be able to exert their activity in particular against microorganisms belonging to some of the species more involved in the development of multidrug resistance.

Prismarenes: A New Class of Macrocyclic Hosts Obtained by Templation in a Thermodynamically Controlled Synthesis.

The novel title macrocycles, based on methylene-bridged 1,5-naphthalene units, have been obtained by template effect in a thermodynamically controlled synthesis. In detail, the prism[5]arene 1 or the prism[6]arene 3 was selectively removed from the equilibrium mixture by using the complementary ammonium-templating agent. When only the solvent 1,2-DCE was used, the 1,4-confused derivative 2 was obtained. The prism[5]arene here described shows a deep π-electron-rich aromatic cavity that exhibits a great affinity for the quaternary ammonium guests, originating from favorable cation···π and +NC-H···π interactions. This recognition motif is the basis of the templated synthesis of the prism[n]arenes here reported.

Synergic Interplay Between Halogen Bonding and Hydrogen Bonding in the Activation of a Neutral Substrate in a Nanoconfined Space.

The principle of amplified halogen bonding (XB) in a small space is exploited as a catalytic tool for the activation of an XB acceptor substrate in a nanoconfined environment. The inner cavity of the resorcinarene capsule has been equipped with an XB catalyst bearing an ammonium unit acting as a Trojan horse to drive the catalyst inside the capsule. In the presence of a specific XB catalyst, the capsule is able to catalyze a Michael reaction between N-methylpyrrole and methyl vinyl ketone. In the bulk medium in absence of the resorcinarene capsule, the XB catalyst is catalytically ineffective. Quantum-mechanical investigations highlight that the Michael reaction proceeds through the activation of the carbonyl group by synergistically enhanced halogen/hydrogen-bonding interactions and takes place in an open pentameric capsule.

The Hexameric Resorcinarene Capsule as a Brønsted Acid Catalyst for the Synthesis of Bis(heteroaryl)methanes in a Nanoconfined Space.

Herein, we show that the hexameric resorcinarene capsule C is able to catalyze the formation of bis(heteroaryl)methanes by reaction between pyrroles or indoles and carbonyl compounds (α-ketoesters or aldehydes) in excellent yields and selectivity. Our results suggest that the capsule can play a double catalytic role as a H-bond catalyst, for the initial activation of the carbonyl substrate, and as a Brønsted acid catalyst, for the dehydration of the intermediate alcohol.

Multiple threading of a triple-calix[6]arene host.

The synthesis of the triple-calix[6]arene derivative 6 in which three calix[6]arene macrocycles are linked to a central 1,3,5-trimethylbenzene moiety is reported. Derivative 6 is able to give multiple-threading processes in the presence of dialkylammonium axles. The formation of pseudo[2]rotaxane, pseudo[3]rotaxane, and pseudo[4]rotaxane by threading one, two, and three, respectively, calix-wheels of 6 has been studied by 1D and 2D NMR, DOSY, and ESI-FT-ICR MS/MS experiments. The use of a directional alkylbenzylammonium axle led to the stereoselective formation of endo-alkyl pseudo[n]rotaxane stereoisomers.