ß-Carboline-based light and pH dual stimuli-responsive ion transporters induce cancer cell death.

Light and pH dual-responsive ion transporters offer better applicability for cancer due to higher tunability and low cytotoxicity. Herein, we demonstrate the development of pH-responsive ß-carboline-based ionophores and photocleavable-linker appended ß-carboline-based proionophores to facilitate the controlled transport of Cl- across membranes, leading to apoptotic and autophagic cancer cell death.

Electrochemical and statistical study of Nickel ion assessment in daily children intake samples relying on magnesium aluminate spinel nanoparticles.

Lately, children's daily consumption of some products, such as cereals and candies, has been rising, which provides a compelling rationale for determining any metallic substances that may be present. Monitoring the concentration of certain metals, like nickel, in these products is necessary due to medical issues in humans when consumed regularly. So, in this work, a novel and highly selective carbon paste as a Ni(II) ion-selective sensor was prepared and investigated using ceramic magnesium aluminum spinel nanoparticles as the ionophore and tritolyl phosphate (TOCP) as a plasticizer. A modified co-precipitation method was used to synthesize the spinel nanoparticles. X-ray diffraction, scanning electron microscope with EDAX, transmission electron microscope, and BET surface area were used to determine the phase composition, microstructure, pores size, particle size, and surface area of the synthesized nanoparticles. The spinel nanoparticle was found to have a nano crystallite size with a cubic crystal system, a particle size ranging from 17.2 to 51.52 nm, mesoporous nature (average pore size = 8.72 nm), and a large surface area (61.75 m2/g). The composition ratio of graphite carbon as a base: TOCP as binder: spinal as ionophore was 67.3:30.0:2.7 (wt%) based on potentiometric detections over concentrations from 5.0 × 10-8 to 1.0 × 10-2 mol L-1 with LOD of 5.0 × 10-8 mol L-1. A measurement of 29.22 ± 0.12 mV decade-1 over pH 2.0-7.0 was made for the Nernstian slope. This sensor demonstrated good repeatability over nine weeks and a rapid response of 8 s. A good selectivity was shown for Ni(II) ions across many interferents, tri-, di-, and monovalent cations. The Ni(II) content in spiked real samples, including cocaine, sweets, coca, chocolate, carbonated drinks, cereals, and packages, were measured. The results obtained indicated no significant difference between the proposed potentiometric method and the officially reported ICP method according to the F- and t-test data. In addition to utilizing ANOVA statistical analysis, validation procedures have been implemented, and the results exceed the ICP-MS methodology.

Anti-Coronavirus Potential of Polyether Ionophores: The New Application of Veterinary Antibiotics in Livestock.

Coronaviruses have consistently posed a major global concern in the field of livestock industry and public health. However, there is currently a lack of efficient drugs with broad-spectrum antiviral activity to address the challenges presented by emerging mutated strains or drug resistance. Additionally, the method for identifying multitarget drugs is also insufficient. Aminopeptidase N (APN) and 3C-like proteinase (3CLpro) represent promising targets for host-directed and virus-directed strategies, respectively, in the development of effective drugs against various coronaviruses. In this study, maduramycin ammonium demonstrated a broad-spectrum antiviral effect by targeting both of the proteins. The binding domains 4 Å from the ligand of both target proteins shared a structural similarity, suggesting that screening and designing drugs based on these domains might exhibit broad-spectrum and highly effective antiviral activity. Furthermore, it was identified that the polyether ionophores' ability to carry zinc ion might be one of the reasons why they were able to target APN and exhibit antiviral effect. The findings of this experiment provide novel perspectives for future drug screening and design, while also offering valuable references for the utilization of polyether ionophores in the management of livestock health.

Responsive Anionophores with AND Logic Multi-Stimuli Activation.

Artificial ion transport systems have emerged as an important class of compounds that promise applications in chemotherapeutics as anticancer agents or to treat channelopathies. Stimulus-responsive systems that offer spatiotemporally controlled activity for targeted applications remain rare. Here we utilize dynamic hydrogen bonding interactions of a 4,6-dihydroxy-isophthalamide core to generate a modular platform enabling access to stimuli-responsive ion transporters that can be activated in response to a wide variety of external stimuli, including light, redox, and enzymes, with excellent OFF-ON activation profiles. Alkylation of the two free hydroxyl groups with stimulus-responsive moieties locks the amide bonds through intramolecular hydrogen bonding and hence makes them unavailable for anion binding and transport. Triggering using a particular stimulus to cleave both cages reverses the hydrogen bonding arrangement, to generate a highly preorganized anion binding cavity for efficient transmembrane transport. Integration of two cages that are responsive to orthogonal stimuli enables multi-stimuli activation, where both stimuli are required to trigger transport in an AND logic process. Importantly, the strategy provides a facile method to post-functionalize the highly active transporter core with a variety of stimulus-responsive moieties for targeted activation with multiple triggers.

The Biological Activities of Polyether Ionophore Antibiotic Routiennocin is Independent of Absolute Stereochemistry.

Carboxylic polyether ionophores (CPIs) are among the most prevalent agricultural antibiotics (notably in the US) and these compounds have been in use for decades. The potential to reposition CPIs beyond veterinary use, e. g. through chemical modifications to enhance their selectivity window, is an exciting challenge and opportunity, considering their general resilience towards resistance development. Given the very large societal impact of these somewhat controversial compounds, it is surprising that many aspects of their mechanisms and activities in cells remain unclear. Here, we report comparative biological activities of the CPI routiennocin and two stereoisomers, including its enantiomer. We used an efficient convergent synthesis strategy to access the compounds and conducted a broad survey of antibacterial activities against planktonic cells and biofilms as well as the compounds' effects on mammalian cells, the latter assessed both via standard cell viability assays and broad morphological profiling. Interestingly, similar bioactivity of the enantiomeric pair was observed across all assays, strongly suggesting that chiral interactions do not play a decisive role in the mode of action. Overall, our findings are consistent with a mechanistic model involving highly dynamic behaviour of CPIs in biological membranes.

Pb2+-Selective Nanoemulsion-Integrated Single-Entity Electrochemistry for Ultrasensitive Sensing of Blood Lead.

Unequivocally, Pb2+ as a harmful substance damaging children's brain and nerve systems, thereby causing behavior and learning disabilities, should be detected much lower than the elevated blood lead for children, 240 nM, endorsed by US CDC considering the unknown neurotoxic effects, yet the ultralow detection limit up to sub-ppb level remains a challenge due to the intrinsically insufficient sensitivity in the current analytical techniques. Here, we present nanoemulsion (NE)-integrated single-entity electrochemistry (NI-SEE) toward ultrasensitive sensing of blood lead using Pb-ion-selective ionophores inside a NE, i.e., Pb2+-selective NE. Through the high thermodynamic selectivity between Pb2+ and Pb-ionophore IV, and the extremely large partition coefficient for the Pb2+-Pb-ionophore complex inside NEs, we modulate the selectivity and sensitivity of NI-SEE for Pb2+ sensing up to an unprecedentedly low detection limit, 20 ppt in aqueous solutions, and lower limit of quantitation, 40 ppb in blood serums. This observation is supported by molecular dynamics simulations, which clearly corroborate intermolecular interactions, e.g., H-bonding and π*-n, between the aromatic rings of Pb-ionophore and lone pair electrons of oxygen in dioctyl sebacate (DOS), plasticizers of NEs, subsequently enhancing the current intensity in NI-SEE. Moreover, the highly sensitive sensing of Pb2+ is enabled by the appropriate suppression of hydroxyl radical formation during NI-SEE under a cathodic potential applied to a Pt electrode. Overall, the experimentally demonstrated NI-SEE approach and the results position our new sensing technology as potential sensors for practical environmental and biomedical applications as well as a platform to interrogate the stoichiometry of target ion-ionophore recognition inside a NE as nanoreactors.

Ionophore-modified polyaniline-based optode for the determination of hydrogen sulfite levels in beverages, wastewater, and soil.

Sulfite is a very important species, affecting human health, plant and animal life, and environmental sustainability. In this study, for the first time, an ionophore-based ion-selective optode was constructed for hydrogen sulfite determination in beverages, such as Birell® and Sprite®, water, and soil samples; instead of normal pH-chromoionophores, polyaniline film was precipitated on a glass slide and used for the transduction of the sensation mechanism. The ionophore-modified polyaniline-based optode incorporated thiourea derivative as an ionophore and tridodecyl methyl ammonium chloride as an ion-exchanger. The optode film was prepared in situ with a modified chemical polymerization method, and it was characterized using atomic force microscopy (AFM), scanning electron microscopy (SEM), and X-ray diffraction (XRD); also, FTIR spectroscopy was performed for the film before and after interaction with hydrogen sulfite for mechanism elucidation. The optode was applied in the hydrogen sulfite concentration range of 10-1 to 10-5 M with a low detection limit of 8.0 × 10-6 M and minimum interference of other interfering species, such as salicylate, iodide, and sulphide. The response mechanism was due to the ion-exchange of hydrogen sulfite with the anion exchanger, followed by the molecular recognition between thiourea ionophore and hydrogen sulfite, with concomitant redox reaction via the protonation of the polyaniline that causes a decrease in absorbance at 685 nm. The optode was applied successfully for the determination of hydrogen sulfite in real beverages, Birell® and Sprite® without any pretreatment steps. Also, it was applied successfully for the environmental monitoring of hydrogen sulfite in real wastewater and soil samples.

Stimuli-responsive release of active anionophore from RGD-peptide-linked proanionophore.

Integrin-mediated cellular delivery was attempted to optimize practical applications of hydrophobic ionophores. The potent ionophore preferentially transports H+/Cl- across the lipid bilayers following a symport mechanism. The RGD-peptide-appended tag was stimulated by glutathione to generate the active ionophore, prompting the transport of Cl- under the cellular environment.

Ultrasensitive Ionophore-Based Liquid Sensors for Colorimetric Ion Measurements in Blood.

The self-monitoring of electrolytes using a small volume of capillary blood is needed for the management of many chronic diseases. Herein, we report an ionophore-based colorimetric sensor for electrolyte measurements in a few microliters of blood. The sensor is a pipet microtip preloaded with a segment of oil (plasticizer) containing a pH-sensitive chromoionophore, a cation exchanger, and an ionophore. The analyte is extracted from the sample into the oil via a mixing protocol controlled by a stepper motor. The oil with an optimized ratio of sensing chemicals shows an unprecedentedly large color response for electrolytes in a very narrow concentration range that is clinically relevant. This ultrahigh sensitivity is based on an exhaustive response mode with a novel mechanism for defining the lower and higher limits of detection. Compared to previous optodes and molecular probes for ions, the proposed platform is especially suitable for at-home blood electrolyte measurements because (1) the oil sensor is interrogated independent of the sample and therefore works for whole blood without requiring plasma separation; (2) the sensor does not need individual calibration as the consistency between liquid sensors is high compared to solid sensors, such as ion-selective electrodes and optodes; and (3) the sensing system consisting of a disposable oil sensor, a programmed stepper motor, and a smartphone is portable, cost-effective, and user-friendly. The accuracy and precision of Ca2+ sensors are validated in 51 blood samples with varying concentrations of total plasma Ca2+. Oil sensors with an ultrasensitive response can also be obtained for other ions, such as K+.

Potentiometric Sensing of Nonsteroidal Painkillers by Acyclic Squaramide Ionophores.

We report here a small library of a new type of acyclic squaramide receptors (L1-L5) as selective ionophores for the detection of ketoprofen and naproxen anions (KF- and NS-, respectively) in aqueous media. 1H NMR binding studies show a high affinity of these squaramide receptors toward KF- and NS-, suggesting the formation of H-bonds between the two guests and the receptors through indole and -NH groups. Compounds L1-L5 have been tested as ionophores for the detection of KF- and NS- inside solvent PVC-based polymeric membranes. The optimal membrane compositions were established through the careful variation of the ligand/tridodecylmethylammonium chloride (TDMACl) anion-exchanger ratio. All of the tested acyclic squaramide receptors L1-L5 have high affinity toward KF- and NS- and anti-Hofmeister selectivity, with L4 and L5 showing the highest sensitivity and selectivity to NS-. The utility of the developed sensors for a high precision detection of KF- in pharmaceutical compositions with low relative errors of analysis (RSD, 0.99-1.4%) and recoveries, R%, in the range 95.1-111.8% has been demonstrated. Additionally, the chemometric approach has been involved to effectively discriminate between the structurally very similar KF- and NS-, and the possibility of detecting these analytes at concentrations as low as 0.07 µM with R2 of 0.947 and at 0.15 µM with R2 of 0.919 for NS- and KF-, respectively, was shown.

Novel Cerium(IV) Coordination Compounds of Monensin and Salinomycin.

The largely uncharted complexation chemistry of the veterinary polyether ionophores, monensic and salinomycinic acids (HL) with metal ions of type M4+ and the known antiproliferative potential of antibiotics has provoked our interest in exploring the coordination processes between MonH/SalH and ions of Ce4+. (1) Methods: Novel monensinate and salinomycinate cerium(IV)-based complexes were synthesized and structurally characterized by elemental analysis, a plethora of physicochemical methods, density functional theory, molecular dynamics, and biological assays. (2) Results: The formation of coordination species of a general composition [CeL2(OH)2] and [CeL(NO3)2(OH)], depending on reaction conditions, was proven both experimentally and theoretically. The metal(IV) complexes [CeL(NO3)2(OH)] possess promising cytotoxic activity against the human tumor uterine cervix (HeLa) cell line, being highly selective (non-tumor embryo Lep-3 vs. HeLa) compared to cisplatin, oxaliplatin, and epirubicin.

Polyether Ionophore Antibiotics Target Drug-Resistant Clinical Isolates, Persister Cells, and Biofilms.

Polyether ionophores are complex natural products known to transport various cations across biological membranes. While several members of this family are used in agriculture (e.g., as anti-coccidiostats) and have potent antibacterial activity, they are not currently being pursued as antibiotics for human use. Polyether ionophores are typically grouped as having similar functions, despite the fact that they significantly differ in structure; for this reason, how their structure and activity are related remains unclear. To determine whether certain members of the family constitute particularly interesting springboards for in-depth investigations and future synthetic optimization, we conducted a systematic comparative study of eight different polyether ionophores for their potential as antibiotics. This includes clinical isolates from bloodstream infections and studies of the compounds' effects on bacterial biofilms and persister cells. We uncover distinct differences within the compound class and identify the compounds lasalocid, calcimycin, and nanchangmycin as having particularly interesting activity profiles for further development. IMPORTANCE Polyether ionophores are complex natural products used in agriculture as anti-coccidiostats in poultry and as growth promoters in cattle, although their precise mechanism is not understood. They are widely regarded as antimicrobials against Gram-positive bacteria and protozoa, but fear of toxicity has so far prevented their use in humans. We show that ionophores generally have very different effects on Staphylococcus aureus, both in standard assays and in more complex systems such as bacterial biofilms and persister cell populations. This will allow us to focus on the most interesting compounds for future in-depth investigations and synthetic optimizations.

Plant-derived chelators and ionophores as potential therapeutics for metabolic diseases.

Transition metal dysregulation is associated with a host of pathologies, many of which are therapeutically targeted using chelators and ionophores. Chelators and ionophores are used as therapeutic metal-binding compounds which impart biological effects by sequestering or trafficking endogenous metal ions in an effort to restore homeostasis. Many current therapies take inspiration or derive directly from small molecules and peptides found in plants. This review focuses on plant-derived small molecule and peptide chelators and ionophores that can affect metabolic disease states. Understanding the coordination chemistry, bioavailability, and bioactivity of such molecules provides the tools to further research applications of plant-based chelators and ionophores.

Na+/K+ carrier ionophore antibiotics valinomycin and monensin enhance the antibacterial activity of fluoride.

Fluoride is routinely used as a highly effective antibacterial agent that interferes with bacterial metabolism through fundamentally different mechanisms. One of the major bacterial evasion mechanisms against fluoride is the impermeability of cell envelope to the anion that limits its cellular uptake. Therefore, translating such compounds to clinical settings requires novel mechanisms to facilitate the uptake of membrane-impermeant molecules. Published data have indicated antibiotic synergy between fluoride and membrane destabilizing agents that induce strong fluoride toxicity in bacteria via enhancing the permeability of bacterial membranes to fluoride. Here, we report a similar mechanism of antibiotic synergy between fluoride and potassium ion carriers, valinomycin and monensin against Gram-positive bacteria, B. subtilis and S. aureus. Molecular dynamics simulations were performed to understand the effect of potassium on the binding affinity of fluoride to monensin and valinomycin. The trajectory results strongly indicated that the monensin molecules transport fluoride ions across the cell membrane via formation of ion-pair between the monensin-K+ complex and a fluoride. This study provides new insights to design novel compounds to enhance the uptake of small toxic anions via synergistic interactions and thus exert strong antibacterial activity against a wide variety of pathogens.

History of Cobaltabis(dicarbollide) in Potentiometry, No Need for Ionophores to Get an Excellent Selectivity.

This work is a mini-review highlighting the relevance of the θ metallabis(dicarbollide) [3,3'-Co(1,2-C2B9H11)2]- with its peculiar and differentiating characteristics, among them the capacity to generate hydrogen and dihydrogen bonds, to generate micelles and vesicles, to be able to be dissolved in water or benzene, to have a wide range of redox reversible couples and many more, and to use these properties, in this case, for producing potentiometric membrane sensors to monitor amine-containing drugs or other nitrogen-containing molecules. Sensors have been produced with this monoanionic cluster [3,3'-Co(1,2-C2B9H11)2]-. Other monoanionic boron clusters are also discussed, but they are much fewer. It is noteworthy that most of the electrochemical sensor species incorporate an ammonium cation and that this cation is the species to be detected. Alternatively, the detection of the borate anion itself has also been studied, but with significantly fewer examples. The functions of the borate anion in the membrane are different, even as a doping agent for polypyrrole which was the conductive ground on which the PVC membrane was deposited. Apart from these cases related to closo borates, the bulk of the work has been devoted to sensors in which the θ metallabis (dicarbollide) [3,3'-Co(1,2-C2B9H11)2]- is the key element. The metallabis (dicarbollide) anion, [3,3'-Co(1,2-C2B9H11)2]-, has many applications; one of these is as new material used to prepare an ion-pair complex with bioactive protonable nitrogen containing compounds, [YH]x[3,3'-Co(1,2-C2B9H11)2]y as an active part of PVC membrane potentiometric sensors. The developed electrodes have Nernstian responses for target analytes, i.e., antibiotics, amino acids, neurotransmitters, analgesics, for some decades of concentrations, with a short response time, around 5 s, a good stability of membrane over 45 days, and an optimal selectivity, even for optical isomers, to be used also for real sample analysis and environmental, clinical, pharmaceutical and food analysis.

Non-Enzymatic Phenylboronic Acid-Based Optode Membrane for Glucose Monitoring in Serums of Diabetic Patients and in the Culture Medium of Human Embryos.

Monitoring glucose levels is important not only for diabetics, but also for tracking embryonic development in human embryo culture media. In this study, an optochemical sensor (glucose-selective polymer membrane) was fabricated for the determination of glucose in serum from diabetic patients and the culture media of human embryos. The optode membranes were formulated using polyvinyl chloride (PVC) as the polymer matrix and 4',5'-dibromofluorescein octadecyl ester (ETH 7075) as the chromoionophore. The sensitivity of the optode membranes was optimized using two different plasticizers (tricresyl phosphate-TCP and nitrophenyloctyl ether-NOPE) and three ionophores (nitrophenylboronic acid-NPBA, trifluorophenyboronic acid-TFPBA, 4'-nitrobenzo-15-crown-5) and tested for glucose detection. The best optode membrane was formulated from 49.5% PVC, 49.5% TCP, 1% NPBA, and 1% ETH 7075. It showed a linear dynamic range of 10-3 M to 10-1 M, with a detection limit of 9 × 10-4 M and a response time of 2 min. The detection mechanism involves H-bonding between NPBA and glucose, which was confirmed by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR). The reaction also involves the formation of boronate esters in basic media with deprotonation of the chromoionophore (ETH 7075), leading to a decrease in UV-Vis absorbance at λmax = 530 nm. The membrane optode was used for glucose determination in synthetic culture medium, commercial embryo culture medium (GLOBAL® TOTAL® W/HEPES), and serum from normal and diabetic patients, showing good accuracy and precision of the optode.

Highly Selective Potentiometric Sensing of Biologically Relevant Pyrophosphate and Lysophosphatidic Acid Using N-Alkyl/Aryl Ammonium Resorcinarenes/Extended-Resorcinarenes as Ionophores.

The ionophore properties of four kinds of N-alkyl/aryl ammonium resorcinarenes and extended-resorcinarenes were inspected for the first time to fabricate polymeric membrane electrodes for determination of biologically relevant pyrophosphate (PPi) and lysophosphatidic acid (LPA). The proposed ion selective electrodes (ISEs) showed significant preference for PPi and LPA with significant selectivity pattern differences from the Hofmeister series. To gain further insight into the performances of the developed ISEs, the binding constants of ionophore-anion complexes in the plasticized membrane phase were investigated, along with the optimized geometries and calculated electrostatic potential. Nernstian potential responses with good reversibility to target anions can be observed when shifting the optimized membranes in aqueous solutions in the concentration range from 10-6.5 to 10-2.3/10-2.2 M. Moreover, potentiometric sensings of PPi and LPA in mineral water and artificial serum were achieved in low µM concentration range, demonstrating their promising real-world applications. These results provide a promising avenue for the development of polymeric membrane electrodes for biological relevant anions and will broaden the scope of potentiometric sensing.

Anchoring H-Bond Donating/Accepting Pyrrolic Derivatives on Preorganized Scaffolds: Conformationally Switchable Bipedal/Tripodal and Locked Molecular Cage Ionophores for Potentiometric Sensing of Phosphate and Fluoride.

The ionophore properties of a myriad of conformationally switchable bipedal/tripodal receptors and locked molecular cages were evaluated here for the first time to fabricate potentiometric sensors for the determination of environmentally important phosphate and fluoride. Owing to the competent ionophore properties such as high binding selectivity and affinity, the developed ion-selective electrodes displayed response preference for phosphate and fluoride with a selectivity pattern that differs distinctly from traditional Hofmeister series. Binding constants of the ionophore-anion complexes are determined to underscore how modifications in the preorganization and H-bond donating/accepting ability of a given series of ionophores can be exploited to improve the performance for potentiometric sensing. While conformationally switchable bipedal/tripodal ionophores prefer tetrahedral oxyanions, locked molecular cages shift their preference to spherical halides gradually. Nernstian potential responses with good reversibility to target anions can be observed when shifting the optimized membrane electrodes in aqueous solutions within the concentration range of 10-6.5-10-2.0 M. Moreover, potentiometric determination of phosphate and fluoride in mineral water, soil, and tap water samples was achieved in a low µM concentration range with high accuracy, confirming their promising utility in real world applications.

Trihexyltetradecylphosphonium chloride based ratiometric fluorescent nanosensors for multiplex anion discrimination.

Compared with the well-studied cations, the development of methods for anion detection is relatively slow due to the anion characteristics such as a complex geometry, strong hydration and a low charge density. Herein, a colorimetric and ratiometric fluorescent anion sensing platform based on trihexyltetradecylphosphonium chloride ([THTP][Cl]) was developed for the first time. Such nanosensors exhibited a pH response of 5-7 as well as a high selectivity to perchlorate. The selectivity behavior followed the Hofmeister series in which lipophilic anions were more readily co-extracted. To deviate from the Hofmeister series, anion ionophores should be introduced for selective complexation of the target anions. As a proof of concept, the organomercury compounds ETH9033 and ETH9009 were employed as model ionophores. The obtained nitrate- and chloride-selective [THTP][Cl]-based nanosensors demonstrated prominent colorimetric and spectroscopic transformations specifically induced by the anion species. The fluorescence (I675/I600) and absorbance (A650/A500) intensities versus the logarithm values of anion concentrations proved a high selectivity towards the major anion. The excellent performance such as high selectivity, good sensitivity and fast response times enabled the accurate determination of nitrate in mineral water. More importantly, through simply altering the ionophores, a pool of [THTP][Cl]-based anion-selective nano-optodes for extended targets could be achieved. The nanosensor shows great potential for anion determination in the environmental and biomedical fields.

Embedding of Functionalized Coordination Cages and a Molecular Knot in a Polymeric Membrane for Potentiometric Sensing of Environmentally Important Oxyanions and Halides.

Three kinds of coordination cages and a molecular knot with inductively activated +P-H, N-H, or C-H hydrogen bond donors anchoring in the functionalized cavities were inspected as ionophores to develop polymeric membrane ISEs for potentiometric sensing of environmentally important oxyanions and halides. The proposed ISEs displayed significant preference for perrhenate, phosphate, or chloride with a selectivity pattern distinctively different from the sequence depending on the Gibbs free energy of hydration owing to the high degree of shape, charge, and size selectivity originating from the rigidity and complementarity of the binding cavities. To gain further insight into the response characters of the proposed ISEs, the binding constants of ionophore-anion complexes in the membrane phase were investigated, and the binding affinity, together with the Hofmeister series, correlates well with the determined selectivity pattern of the proposed ISEs. Optimizing the composition of the membrane such as lipophilic additives and plasticizers produced ISEs displaying Nernstian/near-Nernstian potentiometric responses to primary anions with a wide linear range, improved detection limits, good reversibility, and satisfying lifetime. Potentiometric determination of perrhenate, phosphate, and chloride in river water, mineral water, and artificial serum samples was achieved with good recovery and accuracy using the proposed ISEs, demonstrating their potential for real-life applications. These results will shed new light on how novel ionophores could be designed for potentiometric sensing and broaden the scope of host-guest chemistry of coordination cages and molecular knots.