Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii.

The limited diversity in targets of available antibiotic therapies has put tremendous pressure on the treatment of bacterial pathogens, where numerous resistance mechanisms that counteract their function are becoming increasingly prevalent. Here, we utilize an unconventional anti-virulence screen of host-guest interacting macrocycles, and identify a water-soluble synthetic macrocycle, Pillar[5]arene, that is non-bactericidal/bacteriostatic and has a mechanism of action that involves binding to both homoserine lactones and lipopolysaccharides, key virulence factors in Gram-negative pathogens. Pillar[5]arene is active against Top Priority carbapenem- and third/fourth-generation cephalosporin-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, suppressing toxins and biofilms and increasing the penetration and efficacy of standard-of-care antibiotics in combined administrations.

The "Nitrogen Effect": Complexation with Macrocycles Potentiates Fused Heterocycles to Form Halogen Bonds in Competitive Solvents.

Weak intermolecular forces are typically very difficult to observe in highly competitive polar protic solvents as they are overwhelmed by the quantity of competing solvent. This is even more challenging for three-component ternary assemblies of pure organic compounds. In this work, we overcome these complications by leveraging the binding of fused aromatic N-heterocycles in an open resorcinarene cavity to template the formation of a three-component halogen-bonded ternary assembly in a protic polar solvent system.

Divalent Benzimidazolium-Based Axles for Self-Reporting Pseudorotaxanes.

Mono- and (bis)benzimidazoliums were evaluated both experimentally and computationally for their potential as pseudopolyrotaxane axle building blocks. Their aggregation and photophysical behavior, along with their potential to form a [2]pseudorotaxane with dibenzyl-24-crown-8, was studied through the synergistic application of 1D/2D and diffusion-ordered NMR spectroscopy, mass spectrometry, ultraviolet-visible and fluorescence spectroscopy, and time-dependent density functional theory. Their photophysical behavior was measured and modeled as a function of protonation state, solvent, and concentration.

Naphthalene-functionalized resorcinarene as selective, fluorescent self-quenching sensor for kynurenic acid.

Kynurenic acid is a by-product of tryptophan metabolism in humans, with abnormal levels indicative of disease. There is a need for water-soluble receptors that selectively bind kynurenic acid, allowing for detection and quantification. We report here the high-affinity binding of kynurenic acid in aqueous media to a resorcinarene salt receptor decorated with four flexible naphthalene groups at the upper rim.

Simultaneous Organic and Inorganic Host-Guest Chemistry within Pillararene-Protein Cage Frameworks.

Invited for the cover of this issue are Mauri A. Kostiainen and co-workers at Aalto and Oakland Universities. The image depicts two ferritin protein cages joined by a cationic pillararene hosting a guest dye.

Simultaneous Organic and Inorganic Host-Guest Chemistry within Pillararene-Protein Cage Frameworks.

Supramolecular self-assembly of biomolecules provides a powerful bottom-up strategy to build functional nanostructures and materials. Among the different biomacromolecules, protein cages offer various advantages including uniform size, versatility, multi-modularity, and high stability. Additionally, protein cage crystals present confined microenvironments with well-defined dimensions.

Functionalized resorcinarenes effectively disrupt the aggregation of αA66-80 crystallin peptide related to cataracts.

Cataracts, an eye lens clouding disease, are debilitating and while operable, remain without a cure. αA66-80 crystallin peptide abundant in cataracted eye lenses contributes to aggregation of αA-crystallin protein leading to cataracts. Inspired by the versatility of macrocycles and programmable guest selectivity through discrete functionalizations, we report on three water-soluble ionic resorcinarene receptors (, , and ) that disrupt the aggregation of αA66-80 crystallin peptide.

Recent Advances in Halogen Bonded Assemblies with Resorcin[4]arenes.

Resorcinarenes are cavity-containing compounds when in the crown conformation, from the calixarene family of concave compounds. These easy to synthesize macrocycles can be decorated at the upper rim through the eight hydroxyl groups and/or the 2-position of the aromatic ring. They are good synthons in supramolecular chemistry leading to appealing assemblies such as open-inclusion complexes, capsules and tubes through multiple weak interactions with various guests.

Bringing a Molecular Plus One: Synergistic Binding Creates Guest-Mediated Three-Component Complexes.

C-2-methylresorcinarene (), pyridine (), and a set of 10 carboxylic acids () associate to form ternary assemblies with 1:1:1 stoichiometry, representing a useful class of ternary systems where the guest mediates complex formation between the host and a third component. Although individually weak in solution, the combined strength of the multiple noncovalent interactions organizes the complexes even in a highly hydrogen-bond competing methanol solution, as explored by both experimental and computational methods. The interactions between and are dependent on the p values of carboxylic acids.

Thermodynamically driven self-assembly of pyridinearene to hexameric capsules.

Pyridinearene macrocycles have previously shown unique host-guest properties in their capsular dimers including endo complexation of neutral molecules and exo complexation of anions. Here, we demonstrate for the first time the formation of hydrogen bonded hexamer of tetraisobutyl-octahydroxypyridinearene in all three states of matter - gas phase, solution and solid-state. Cationic tris(bipyridine)ruthenium(ii) template was found to stabilize the hexamer in gas phase, whereas solvent molecules do this in condensed phases.

Halogen bonding and host-guest chemistry between -alkylammonium resorcinarene halides, diiodoperfluorobutane and neutral guests.

Single crystal X-ray structures of halogen-bonded assemblies formed between host -hexylammonium resorcinarene bromide () or -cyclohexylammonium resorcinarene chloride (), and 1,4-diiodooctafluorobutane and accompanying small solvent guests (methanol, acetonitrile and water) are presented. The guests' inclusion affects the geometry of the cavity of the receptors and , while the divalent halogen bond donor 1,4-diiodooctafluorobutane determines the overall nature of the halogen bond assembly. The crystal lattice of contains two structurally different dimeric assemblies A and B, formally resulting in the mixture of a capsular dimer and a dimeric pseudo-capsule.

Halogen-Bond-Mediated Self-Assembly of Polymer-Resorcinarene Complexes.

A new supramolecular system based on halogen-bonded macromolecular substances is presented. Binding and complex formation between a halogen bond acceptor N-benzyl ammonium resorcinarene bromide and a library of polymeric halogen bond donors based on iodotetrafluorophenoxy functionality is shown. The complex formation was confirmed in liquid state by dynamic light scattering and transmission electron microscopy.

Host-guest complexes of conformationally flexible -hexyl-2-bromoresorcinarene and aromatic -oxides: solid-state, solution and computational studies.

Host-guest complexes of -hexyl-2-bromoresorcinarene (BrC6) with twelve potential aromatic -oxide guests were studied using single crystal X-ray diffraction analysis and H NMR spectroscopy. In the solid state, of the nine obtained X-ray crystal structures, eight were consistent with the formation of BrC6--oxide complexes. The lone exception was from the association between 4-phenylpyridine oxide and BrC6, in that case the host forms a self-inclusion complex.

Crystalline Cyclophane-Protein Cage Frameworks.

Cyclophanes are macrocyclic supramolecular hosts famous for their ability to bind atomic or molecular guests via noncovalent interactions within their well-defined cavities. In a similar way, porous crystalline networks, such as metal-organic frameworks, can create microenvironments that enable controlled guest binding in the solid state. Both types of materials often consist of synthetic components, and they have been developed within separate research fields.

A supramolecular host-guest complex for heparin binding and sensing.

Heparin is an anionic polysaccharide widely used in clinics as an anticoagulant. However, heparin usage requires an antidote and sensors for safe operation during and after surgeries. In this study, a host-guest complex capable of selective heparin binding and sensing is presented.

High-affinity and selective detection of pyrophosphate in water by a resorcinarene salt receptor.

Pyrophosphate (PPi) is a byproduct of DNA and RNA synthesis, and abnormal levels are indicative of disease. We report the high-affinity binding of PPi in water by -alkyl ammonium resorcinarene chloride receptors. Experimental analysis using H and P NMR, isothermal titration calorimetry, mass spectrometry, and UV-vis spectroscopy all support exceptional selectivity of these systems for PPi in water.

Self-Complementary Dimers of Oxalamide-Functionalized Resorcinarene Tetrabenzoxazines.

Self-complementarity is a useful concept in supramolecular chemistry, molecular biology and polymeric systems. Two resorcinarene tetrabenzoxazines decorated with four oxalamide groups were synthesized and characterized. The oxalamide groups possessed self-complementary hydrogen bonding sites between the carbonyls and amide groups.

Simultaneous endo and exo Complex Formation of Pyridine[4]arene Dimers with Neutral and Anionic Guests.

The formation of complexes between hexafluorophosphate (PF ) and tetraisobutyloctahydroxypyridine[4]arene has been thoroughly studied in the gas phase (ESI-QTOF-MS, IM-MS, DFT calculations), in the solid state (X-ray crystallography), and in chloroform solution ( H, F, and DOSY NMR spectroscopy). In all states of matter, simultaneous endo complexation of solvent molecules and exo complexation of a PF anion within a pyridine[4]arene dimer was observed. While similar ternary complexes are often observed in the solid state, this is a unique example of such behavior in the gas phase.

Host-Guest Complexes of C-Ethyl-2-methylresorcinarene and Aromatic ,'-Dioxides.

The C-ethyl-2-methylresorcinarene () forms 1:1 in-cavity complexes with aromatic ,-dioxides, only if each of the aromatic rings has an N-O group. The structurally different C-shaped 2,2'-bipyridine ,'-dioxide (2,2'-BiPyNO) and the linear rod-shaped 4,4'-bipyridine ,'-dioxide (4,4'-BiPyNO) both form 1:1 in-cavity complexes with the host resorcinarene in crown and conformations, respectively. In the solid state, the host-guest interactions between the 1,3-bis(4-pyridyl)propane ,'-dioxide (BiPyPNO) and the host stabilize the unfavorable - conformation.

Recognition of Viologen Derivatives in Water by N-Alkyl Ammonium Resorcinarene Chlorides.

Three water-soluble N-alkyl ammonium resorcinarene chlorides decorated with terminal hydroxyl groups at the lower rims were synthesized and characterized. The receptors were decorated at the upper rim with either terminal hydroxyl, rigid cyclohexyl, or flexible benzyl groups. The binding affinities of these receptors toward three viologen derivatives, two of which possess an acetylmethyl group attached to one of the pyridine nitrogens, in water were investigated via H NMR spectroscopy, fluorescence spectroscopy, and isothermal titration calorimetry (ITC).

[N⋅⋅⋅I ⋅⋅⋅N] Halogen-Bonded Dimeric Capsules from Tetrakis(3-pyridyl)ethylene Cavitands.

Two [N⋅⋅⋅I ⋅⋅⋅N] halogen-bonded dimeric capsules using tetrakis(3-pyridyl)ethylene cavitands with different lower rim alkyl chains are synthesized and analyzed in solution and the gas phase. These first examples of symmetrical dimeric capsules making use of the iodonium ion (I ) as the main connecting module are characterized by H NMR spectroscopy, diffusion ordered NMR spectroscopy (DOSY), electrospray ionization mass spectrometry (ESI-MS), and ion mobility-mass spectrometry (TW-IMS) experiments. The synthesis and effective halogen-bonded dimerization proceeds through analogous dimeric capsules with [N⋅⋅⋅Ag ⋅⋅⋅N] binding motifs as the intermediates as evidenced by the X-ray structures of (CH Cl ) @[3 a ⋅Ag ⋅(H O) ⋅OTs ] and (CH Cl ) @[3 a ⋅Ag ⋅(H O) ⋅OTs ], two structurally different capsules.