Zwitterionic Compounds Research Articles

Zwitterionic 2-Phosphaethene-thiolates [(LC)P=CS(LC/P)]+ as PCS Building Blocks (LC=NHC, LP=PR3).

The zwitterionic compounds [(LC)P=CS(LC/P)]+ (3+, LC=NHC, LP=PR3), featuring cationic substituents at the phosphorus and carbon atoms, are synthesized as their triflate salts at a multi-gram scale from the reaction of Lewis base adducts of CS2, namely LC/P-CS2 (4), with a combination of [(LCP)4][OTf]4 (1[OTf]4) and Ph3P. The feasibility of using 3+ as PCS building blocks is showcased in their reactions with representative electrophiles (MeOTf) and nucleophiles (MesMgBr, Ph3PCH2), leading to selective functionalization of the PCS core at the S- and P-terminus, respectively. Additionally, it is reported that 3+ can function as ambident nucleophiles with AgOTf (2 equivalents), affording unprecedented linear coordination polymer [Ag2(OTf)3-μ2:κP,κS-((LC)P=CS(PCy3))]+ (6 b), where the PCS moiety acts as a bridging ligand in transition metal complexes for the first time. Reduction of 3+ facilitates the cleavage of the P- and C-bound substituents leading to the formation of the [PCS]- anion. Moreover, cycloaddition reactions of 3+ with 1[OTf]4 are shown to selectively yield five- and eight-membered polyphosphorus heterocycles. Preliminary results suggest the possibility of activating the C-S bond in [(LC)P=CS(LC)]+, resulting in the formation of [(LC)P=C(LC)-P(LC)][OTf]2, 12[OTf]2, which may serve as a synthon for the PCP unit in future studies.

Zwitterionic 2‐Phosphaethene‐thiolates [(LC)P=CS(LC/P)]+ as PCS Building Blocks (LC = NHC, LP = PR3)

The zwitterionic compounds [(LC)P=CS(LC/P)]+ (3+, LC = NHC, LP = PR3), featuring cationic substituents at the phosphorus and carbon atoms, are synthesized as their triflate salts at a multi‐gram scale from the reaction of Lewis base adducts of CS2, namely LC/P–CS2 (4), with a combination of [(LCP)4][OTf]4 (1[OTf]4) and Ph3P. The feasibility of using 3+ as PCS building blocks is showcased in their reactions with representative electrophiles (MeOTf) and nucleophiles (MesMgBr, Ph3PCH2), leading to selective functionalization of the PCS core at the S‐ and P‐terminus, respectively. Additionally, it is reported that 3+ can function as ambident nucleophiles with AgOTf (2 equivalents), affording unprecedented linear coordination polymer [Ag2(OTf)3‐μ2:κP,κS–((LC)P=CS(PCy3))]+ (6b), where the PCS moiety acts as a bridging ligand in transition metal complexes for the first time. Reduction of 3+ facilitates the cleavage of the P‐ and C‐bound substituents leading to the formation of the [PCS]– anion. Moreover, cycloaddition reactions of 3+ with 1[OTf]4 are shown to selectively yield five‐ and eight‐membered polyphosphorus heterocycles. Preliminary results suggest the possibility of activating the C–S bond in [(LC)P=CS(LC)]+, resulting in the formation of [(LC)P=C(LC)–P(LC)][OTf]2, 12[OTf]2, which may serve as a synthon for the PCP unit in future studies.

Widespread Misinterpretation of pKa Terminology for Zwitterionic Compounds and Its Consequences.

The acid dissociation constant (pKa), which quantifies the propensity for a solute to donate a proton to its solvent, is crucial for drug design and synthesis, environmental fate studies, chemical manufacturing, and many other fields. Unfortunately, the terminology used for describing acid-base phenomena is sometimes inconsistent, causing large potential for misinterpretation. In this work, we examine a systematic confusion underlying the definition of "acidic" and "basic" pKa values for zwitterionic compounds. Due to this confusion, some pKa data are misrepresented in data repositories, including the widely used and highly trusted ChEMBL database. Such datasets are frequently used to supply training data for pKa prediction models, and hence, confusion and errors in the data make the model performance worse. Herein, we discuss the intricacies of this issue. We make suggestions for describing acid-base phenomena, training pKa prediction models, and stewarding pKa datasets, given the high potential for confusion and potentially high impact in downstream applications.

B-286 Single Experiment, Single Plate Solid Phase Extraction (SPE) Optimization using 47 Drug Analytes as an Example

Abstract Background SPE of biological matrices isolates analytes of interest from interfering matrix components that can affect LC-MS/MS quantitation. Optimal SPE conditions are dependent upon the sample matrix and analyte properties and typically require multiple experiments to determine optimal conditions for SPE extraction. Here, a 96-well method development plate was utilized to streamline method development for a panel of 47 clinical research drug analytes: 14 antipsychotics, 22 antidepressants and 11 anticonvulsants. Methods An SPE plate with four polymeric sorbents: reversed phase (X), strong and weak cation-exchange and weak anion-exchange mixed-mode phases (X-C, X-CW and X-AW) was used. The 47 drugs analytes were extracted on all four sorbents using three sets of conditions: acidic pretreatment/wash (aq) with basic elution (AB), neutral pretreatment/wash (aq) with neutral elution (NN), and basic pretreatment/wash (aq) with acidic elution (BA). A 50/50 methanol/water wash was also included. Elution used neutral or pH adjusted ethyl acetate/isopropanol or methanol/acetonitrile. A reagent blank, matrix blank, extracted serum samples spiked post-elution (n=2), and spiked serum (n=4) were extracted on each sorbent using each set of conditions. Optimal conditions were determined by calculating absolute percent recovery for each analyte. Results Recovery for antipsychotics was 85-97% using X-CW-AB, except Chlorpromazine (59%). It had better recovery (80%) using X-AB. Recovery for the antidepressants was 75-112% using X-C-AB, except Bupropion (35%) and Selegiline (10%). Bupropion had better recovery (83% and 95%) using X or X-CW and BA. Selegiline had better recovery using X, X-CW and X-AW with BA (83-92%). Anticonvulsants comprise zwitterionic, sulfonamides, neutral, acidic, and basic compounds with widely varying pKa and polarity. Targeting a single method for these analytes is difficult. The best recovery for anticonvulsants used X-CW-AB with several exceptions. Lacosamide, Felbamate, and Levetiracetam are neutral and among the most polar analytes and had 7-31% recovery under all SPE conditions tested. Zwitterionic Gabapentin and Pregabalin had 50-53% recovery from X-CW and X-C sorbents. The stronger protic elution (ammoniated methanol/acetonitrile vs ethyl acetate/isopropanol ) improved solubility for complete elution. Oxcarbazepine had 37% recovery from X-CW-AB, but recovery was 71% under BA conditions. Neutral, polar Zonisamide and Topiramate (Sulfonamide compounds) recovery was 25-26% using X-CW-AB. However, recovery was better (47% and 83%) under NN conditions, suggesting the analytes didn’t undergo complete elution from the X-CW sorbent. A stronger elution solvent would improve recovery from X-CW. Conclusions Most antipsychotics were recovered with X-CW-AB. Most antidepressants could be extracted using X-C-AB. Some analytes had higher recovery using hydrophobic interaction (X) SPE. A single mixed-mode SPE two-step elution protocol using a stronger elution solvent may be feasible. Anticonvulsants had mixed results. Some would require a stronger elution solvent. Some could be included in the other two panels to maximize recovery, but some had low recovery under all conditions tested. The method development plate screened 12 SPE methods for 47 analytes in a single experiment, greatly reducing the time and labor required to identify the best sorbent and starting conditions for SPE extraction optimization for drug analysis. This workflow could be implemented for other SPE method development projects.

Zwitterionic Energetic Materials: Synthesis, Structural Diversity and Energetic Properties.

Zwitterionic compounds are an emergent class of energetic materials and have gained synthetic interest of many in the recent years. Due to their better packing efficiencies and strong inter/intramolecular electrostatic interactions, they often ensue superior energetic properties than their salt analogues. A systematic review from the perspective of design, synthesis, and physicochemical properties evaluation of the zwitterionic energetic materials is presented. Depending on the parent ring(s) used for the synthesis and the type of moieties bearing positive and negative charges, different classes of energetic materials, such as primary explosives, secondary explosives, heat resistant explosives, oxidizers, etc., may result. The properties of some of the energetic zwitterionic compounds are also compared with analogous energetic salts. This review will encourage readers to explore the possibility of designing new zwitterionic energetic materials.

Proton‐conducting hydrogel electrolytes with tight contact to binder‐free MXene electrodes for high‐performance thermally chargeable supercapacitor

AbstractThermally chargeable supercapacitors (TCSCs) have offered exceptional energy‐converting efficiency for absorbing human epidermal heat and generating and storing electrical energy, which then realize continuous power supply to electronic devices, such as sensors and wearable electronic products, in a wide range of practical significance. Here, we proposed a flexible TCSC by attaching binder‐free Ti3C2Tx MXene@PPy electrodes on both ends of the H3PO4@P(AM‐co‐AA‐co‐AYP K+) hydrogel electrolyte, which exhibits a large thermal power of 35.2 mV K−1 at 50% relative humidity and maximum figure of merit of 2.1. The high performances of the fabricated devices can be attributed to the tunable electrical, thermodynamic, thermoelectric, and mechanical properties of the hydrogel electrolyte by adjusting the acid content and the proportion of zwitterionic compound AYP K+ in the hydrogel, and the high photothermal conversion efficiency and electrochemical performance of the electrodes. Moreover, the stable and outstanding thermofvoltage output (∼200 mV) under different time scenarios of the TCSC makes it possible to drive a strain sensor, accomplishing the objectives of a human activity monitor.

Can membrane permeability of zwitterionic compounds be predicted by the solubility-diffusion model?

Zwitterions contain both positively and negatively charged functional groups, resulting in an overall net neutral charge. Nevertheless, the membrane permeability of the zwitterionic form of a compound is assumed to be much lower than the permeability of the uncharged neutral form. Although a significant proportion of pharmaceuticals are zwitterionic, it has not been clear so far whether their permeability is dominated by the permeation of the zwitterionic or the neutral form, since neutral fractions are often quite low as compared to the zwitterionic fraction. This complicates the in silico prediction of the permeability of zwitterionic compounds. In this work, we re-evaluated existing in vitro permeability data from literature measured with Caco-2/MDCK cell assays, using more strict exclusion criteria for effects like diffusion limitation by the aqueous boundary layers, paracellular transport, active transport and retention. Using this re-evaluated data set, we show that extracted intrinsic permeabilities of the neutral fraction are well predicted by the solubility-diffusion model (RMSE = 1.21; n = 18) if the permeability of the zwitterionic species is assumed negligible. Our work thus suggests that only the neutral species is relevant for the membrane permeability of zwitterionic compounds, and that membrane permeability of zwitterionic compounds is indeed predictable by the solubility-diffusion model.

Immobilized enzymatic membrane surfaces for biocatalytic organics removal and fouling resistance

This research reported on the immobilization of environmentally friendly enzymes, such as horseradish peroxidase (HRP) and laccase (L), along with the hydrophilic zwitterionic compound l-DOPA on nano-filtration (NF) membranes. This approach introduced biocatalytic membranes, leveraging combined effects between membranes and enzymes. The aim was to systematically assess the efficacy of the enzymatic modified membrane (HRP-NF) in degrading colors in the wastewater, as well as enhancing the membrane resistance toward organic fouling. The enzymatic immobilized membrane demonstrated 96.3 ± 1.8% to 96.6 ± 1.9% removal of colors, and 65.2 ± 1.3% to 67.2 ± 1.3% removal of TOC. This result was underpinned by the insights obtained from the radical scavenger coumarin, which was employed to trap and confirm the formation of PRs through the reaction of enzymes and H2O2. Furthermore, membranes modified with enzymes exhibited significantly improved antifouling properties. The HRP-NF membrane experienced an 8% decline in flux, while the co-immobilized HRP-L-NF membrane demonstrated as low as 6% flux decline, contributed by the synergistic effect of increased hydrophilicity and biocatalytic effects. These findings confirmed that the immobilized enzymatic surface has added function of degrading contaminants in addition to separation function of nanofiltration membrane. These l-DOPA-immobilized enzymatic membranes offered a promising hybrid biocatalytic membrane to eliminate dyes and mitigate membrane fouling, which can be applied in many industrial and domestic water and wastewater treatment.

Ligand Exchange at Carbon: Synthetic Entry to Elusive Species and Versatile Reagents.

How different is carbon compared to other elements in the periodic table? Can carbon compounds be regarded as coordination complexes with carbon as the central element undergoing a facile exchange of its ligands? Although carbon clearly plays a special role among the elements of the periodic table, recent studies have drawn parallels between the bonding situation and the reactivity of carbon compounds to transition metal complexes. This Perspective summarizes recent reports about ylidic and zwitterionic compounds that were shown to exhibit ambiguous bonding situations that can be interpreted as donor-acceptor interactions similar to the bond between a metal and a neutral ligand. Based on this conception, ligand exchange reactions prototypical of transition metal complexes were realized at carbon atoms, enabling new synthetic strategies for the synthesis of reactive species and building blocks. In particular, the exchange of N2, CO, and phosphine ligands led to the development of a mild method for accessing new compounds and reagents with unusual properties, such as vinylidene ketenes or stable ketenyl anions, that open up a diverse but still poorly explored follow-up chemistry.

Application of β-Cyclodextrin Adsorbents in the Removal of Mixed Per- and Polyfluoroalkyl Substances.

The extensive use of per- and polyfluoroalkyl substances (PFASs) in industrial consumer products has led to groundwater contamination, raising concerns for human health and the environment. These persistent chemicals exist in different forms with varying properties, which makes their removal challenging. In this study, we assessed the effectiveness of three different β-cyclodextrin (β-CD) adsorbents at removing a mixture of PFASs, including anionic, neutral, and zwitterionic compounds, at neutral pH. We calculated linear partition coefficient (Kd) values to quantify the adsorption affinity of each PFAS. β-CD polymers crosslinked with hexamethylene diisocyanate (β-CD-HDI) and epichlorohydrin (β-CD-EPI) displayed some adsorption of PFASs. Benzyl chloride β-CD (β-CD-Cl), an adsorbent that had not been previously reported, was also synthesized and tested for PFAS adsorption. β-CD-Cl exhibited higher PFAS adsorption than β-CD-HDI and β-CD-EPI, with log Kd values ranging from 1.9 L·g-1 to 3.3 L·g-1. β-CD-Cl displayed no affinity for zwitterionic compounds, as opposed to β-CD-HDI and β-CD-EPI, which removed N-dimethyl ammonio propyl perfluorohexane sulfonamide (AmPr-FHxSA). A comparison between Kd values and the log Kow of PFAS confirmed the significant role of hydrophobic interactions in thee adsorption mechanism. This effect was stronger in β-CD-Cl, compared to β-CD-HDI and β-CD-EPI. While no effect of PFAS charge was observed in β-CD-Cl, some influence of charge was observed in β-CD-HDI and β-CD-EPI, with less negative compounds being more adsorbed. The adsorption of PFASs by β-CD-Cl was similar in magnitude to that of other adsorbents proposed in literature. However, it offers the advantage of not containing fluorine, unlike many commonly proposed adsorbents.

Effect of the Incorporation of Compounds into Digitally Manufactured Dental Materials—A Systematic Review

The aim of this review was to evaluate if the properties of digitally produced dental acrylic resins improved when reinforced with compounds. A literature search was conducted in PubMed, Web of Science, and Scopus databases for the past 10 years. Combinations of keywords were chosen to reflect the PICO question: Do digitally produced dental acrylic resins loaded with compounds have better mechanical, surface and/or biological properties than resins without compounds? The selection was carried out by two independent researchers according to the PRISMA flowchart and specific eligibility criteria. Results: The 19 in vitro studies included dealt with incorporated compounds such as zirconium dioxide nanoparticles, graphene nanoplatelets, and zwitterionic compounds. It was found that some compounds had a negative impact on the mechanical and surface properties, while others showed improvements. Most of the loaded resins had more effective antimicrobial activity compared to the controls. There were also differences in biocompatibility depending on the type of compound incorporated. The compounds affect the mechanical and surface properties of loaded acrylic resins, depending on the type and concentration of the compound. In the case of antimicrobial activity and biocompatibility, the results depended on other factors than the chemical composition of the compound included in the resin.

Zwitterionic Tröger's Base Microfiltration Membrane Prepared via Vapor-Induced Phase Separation with Improved Demulsification and Antifouling Performance.

The fouling of separation membranes has consistently been a primary factor contributing to the decline in membrane performance. Enhancing the surface hydrophilicity of the membrane proves to be an effective strategy in mitigating membrane fouling in water treatment processes. Zwitterionic polymers (containing an equimolar number of homogeneously distributed anionic and cationic groups on the polymer chains) have been used extensively as one of the best antifouling materials for surface modification. The conventional application of zwitterionic compounds as surface modifiers is intricate and inefficient, adding complexity and length to the membrane preparation process, particularly on an industrial scale. To overcome these limitations, zwitterionic polymer, directly used as a main material, is an effective method. In this work, a novel zwitterionic polymer (TB)-zwitterionic Tröger's base (ZTB)-was synthesized by quaternizing Tröger's base (TB) with 1,3-propane sultone. The obtained ZTB is blended with TB to fabricate microfiltration (MF) membranes via the vapor-induced phase separation (VIPS) process, offering a strategic solution for separating emulsified oily wastewater. Atomic force microscopy (AFM), scanning electron microscopy (SEM), water contact angle, and zeta potential measurements were employed to characterize the surface of ZTB/TB blended membranes, assessing surface morphology, charge, and hydrophilic/hydrophobic properties. The impact of varying ZTB levels on membrane surface morphology, hydrophilicity, water flux, and rejection were investigated. The results showed that an increase in ZTB content improved hydrophilicity and surface roughness, consequently enhancing water permeability. Due to the attraction of water vapor, the enrichment of zwitterionic segments was enriched, and a stable hydration layer was formed on the membrane surface. The hydration layer formed by zwitterions endowed the membrane with good antifouling properties. The proposed mechanism elucidates the membrane's proficiency in demulsification and the reduction in irreversible fouling through the synergistic regulation of surface charge and hydrophilicity, facilitated by electrostatic repulsion and the formation of a hydration layer. The ZTB/TB blended membranes demonstrated superior efficiency in oil-water separation, achieving a maximum flux of 1897.63 LMH bar-1 and an oil rejection rate as high as 99% in the oil-water emulsion separation process. This study reveals the migration behavior of the zwitterionic polymer in the membrane during the VIPS process. It enhances our comprehension of the antifouling mechanism of zwitterionic membranes and provides guidance for designing novel materials for antifouling membranes.

Synthesis of (5-Iminio-4,5-dihydro-1,3,4-oxadiazol-2-yl)tetrazol-1-ide: A Zwitterionic Compound Containing a Tetrazole Anion as a Promising Blunt Energetic Material

Abstract(5-Iminio-4,5-dihydro-1,3,4-oxadiazol-2-yl)tetrazol-1-ide is the first zwitterionic energetic material containing tetrazole as an anion and 1,3,4 oxadiazole as a cation. Its low mechanical sensitivity (IS >40 J, FS >360 N) and high gas volume after detonation at standard temperature and pressure (767.0 dm3/kg) make it a prime example of a novel type of blunt energetic material with promising applications.

Dispersion of asphaltene aggregates by zwitterionic surfactants: influence of cations structure

The precipitation and deposition of asphaltenes are significant challenges in the petroleum industry resulting in substantial costs. A practical approach to addressing this issue is to use chemicals as inhabiting and dispersing agents. Zwitterionic surfactants are interesting materials in this field. In this study, three zwitterionic compounds including 2-(1-methyl-1H-imidazol-3-ium-3-yl)butane-1-sulfonate (MIBS), 4-(pyridin-1-ium-1-yl) butane-1-sulfonate (PBS), and 4-(tributylammonio)butane-1-sulfonate (TBBS) were synthesized and characterized by FT-IR, NMR spectroscopy, thermogravimetric, and differential thermal analysis. The ability of these zwitterions to prevent asphaltenes precipitation was investigated using interfacial measurements, ultraviolet spectroscopy, quartz microbalance analysis, particle size analysis, and optical microscopy. The results showed that the MIBS zwitterion, which contains an imidazole cation, was the most effective in dispersing asphaltene aggregates compared to the other two zwitterions. For instance, the UV spectroscopy results showed that the dispersion indexes for MIBS, PBS, and TBBS were 52.8%, 29.9%, and 16.3%, respectively. In addition, the size of asphaltene particles reached from 2179 nm to 622, 1489, and 2038 nm for MIBS, PBS, and TBBS, respectively. Finally, a comparison between the performance of these zwitterions with sodium dodecyl sulfonate (SDS) and tetrabutylammonium hydrogen sulfate (TBAHS) showed the following trend: MIBS (90.5%)> PBS (79.4%) > TBAHS (75%)> SDS (73.9%) >TBBS (46%).

Reactions of cyclonickelated complexes with hydroxylamines and TEMPO˙: isolation of new TEMPOH adducts of Ni(II) and their reactivities with nucleophiles and oxidants.

This contribution describes a study on the reactivities of the complexes [{κP,κC-(i-Pr)2PO-Ar}Ni(μ-Br)]2, 1a-d (Ar: C6H4, a; 3-Cl-C6H3, b; 3-OMe-C6H3, c; 4-OMe-napthalenyl, d), with hydroxylamines in the presence of TEMPO˙ (TEMPO˙ = (2,2,6,6-tetramethylpiperidinyl-1-yl)oxyl). The results of this study showed that treating 1a-d with a mixture of Et2NOH and TEMPO˙ did not afford the desired oxidation-induced functionalization of the Ni-aryl moiety in 1a-d, giving instead the corresponding κO-TEMPOH adducts [{κP,κC-(i-Pr)2PO-Ar}Ni(Br)(κO-TEMPOH)], 3a-d (TEMPOH = N-hydroxy-2,2,6,6-tetramethylpiperidine). The TEMPOH moiety in these zwitterionic compounds 3 can be displaced by a large excess of acetonitrile (MeCN), 10 equiv. of morpholine, or 1-2 equivalents of imidazole. Although these reactions have given the authenticated products [{κP,κC-(i-Pr)2PO-C6H4}Ni(Br)(NCMe)], 4a, [{κP,κC-(i-Pr)2PO-C6H4}Ni(Br)(morpholine)], 5a, and [{κP,κC-(i-Pr)2PO-C6H4}Ni(imidazole)2]Br, 6a, a few other products were also detected by NMR, indicating that the observed reactivities are far more complex than simple substitution of the TEMPOH moiety. Similarly, treating 3a with AgOC(O)CF3 results in the isolation of [{κP,κC-(i-Pr)2PO-C6H4}Ni{OC(O)CF3}(κO-TEMPOH)], 7a, arising from the substitution of the bromo ligand, whereas spectroscopic evidence suggests further reactivity, possibly including displacement of TEMPOH and oxidative decomposition.

Toxicity of Zwitterionic Perfluorinated Compounds in Water Hyacinth

Per- and polyfluoroalkyl substances (PFASs) pollution has become a hot environmental issue. PFASs have been detected in various types of environmental media and biological tissues, and the aquatic environment is an important “sink” for PFASs. As one of the most widely distributed organisms in aquatic environment, plants inevitably contact with PFASs, which may cause toxic effects in aquatic plants. However, most current studies focus on terrestrial plants and animals, but neglect the effects of PFASs in aquatic plants. Therefore, in this study, the freshwater plant, water hyacinth (Eichhornia crassipes), is selected as the research object to explore the toxic effects of zwitterionic perfluorinated compounds on aquatic plants. The results show that low concentration of perfluorooctaneamido betaine (PFOSB) (500 ng/L, 96 h) promotes the net photosynthetic rate of water hyacinth leaves, and the presence of perfluorooctanesulfonamido betaine (PFOAB) and PFOSB cause a significant increase in CAT activity in water hyacinth roots after 48 h. The antioxidant system is activated in response to the PFOAB and PFOSB stresses. This study provides a powerful theoretical basis for the toxic effects and ecological risks of zwitterionic PFASs in aquatic plants.

Accurate prediction of Kp,uu,brain based on experimental measurement of Kp,brain and computed physicochemical properties of candidate compounds in CNS drug discovery

A mathematical equation model was developed by building the relationship between the fu,b/fu,p ratio and the computed physicochemical properties of candidate compounds, thereby predicting Kp,uu,brain based on a single experimentally measured Kp,brain value. A total of 256 compounds and 36 marketed published drugs including acidic, basic, neutral, zwitterionic, CNS-penetrant, and non-CNS penetrant compounds with diverse structures and physicochemical properties were involved in this study. A strong correlation was demonstrated between the fu,b/fu,p ratio and physicochemical parameters (CLogP and ionized fraction). The model showed good performance in both internal and external validations. The percentages of compounds with Kp,uu,brain predictions within 2-fold variability were 80.0 %–83.3 %, and more than 90 % were within a 3-fold variability. Meanwhile, “black box” QSAR models constructed by machine learning approaches for predicting fu,b/fu,p ratio based on the chemical descriptors are also presented, and the ANN model displayed the highest accuracy with an RMSE value of 0.27 and 86.7 % of the test set drugs fell within a 2-fold window of linear regression. These models demonstrated strong predictive power and could be helpful tools for evaluating the Kp,uu,brain by a single measurement parameter of Kp,brain during lead optimization for CNS penetration evaluation and ranking CNS drug candidate molecules in the early stages of CNS drug discovery.

A synthetic approach towards drug modification: 2-hydroxy-1-naphthaldehyde based imine-zwitterion preparation, single-crystal study, Hirshfeld surface analysis, and computational investigation.

The current work is about the modification of primary amine functionalized drugs, pyrimethamine and 4-amino-N-(2,3-dihydrothiazol-2-yl)benzenesulfonamide, via condensation reaction with 2-hydroxy-1-naphthaldehyde to produce new organic zwitterionic compounds (E)-1-(((4-(N-(2,3-dihydrothiazol-2-yl)sulfamoyl)phenyl)iminio)methyl)naphthalen-2-olate (DSPIN) and (E)-1-(((4-amino-5-(4-chlorophenyl)-6-ethylpyrimidin-2-yl)iminio)methyl)naphthalen-2-olate (ACPIN) in methanol as a solvent. The crystal structures of both compounds were confirmed to be imine-based zwitterionic products via single-crystal X-ray diffraction (SC-XRD) analysis which indicated that the stabilization of both crystalline compounds is achieved via various noncovalent interactions. The supramolecular assembly in terms of noncovalent interactions was explored by the Hirshfeld surface analysis. Void analysis was carried out to predict the crystal mechanical response. Compound geometries calculated in the DFT (Density Functional Theory) study showed reasonably good agreement with the experimentally determined structural parameters. Frontier molecular orbital (FMO) analysis showed that the DSPIN HOMO/LUMO gap is by 0.15 eV smaller than the ACPIN HOMO/LUMO gap due to some destabilization of the DSPIN HOMO and some stabilization of its LUMO. The results of the charge analysis implied formation of intramolecular hydrogen bonds and suggested formation of intermolecular hydrogen bonding and dipole-dipole and dispersion interactions.

Zwitterionic fused pyrazolo-triazole based high performing energetic materials.

A series of nitrogen-rich fused energetic materials were synthesized from commercially available inexpensive starting materials and fully characterized using 1H and 13C NMR, IR spectroscopy, elemental analysis, and DSC. The structure of zwitterionic compound 2 was supported by SCXRD data. Among all, 3 and 4 possess excellent detonation velocity (8956 and 9163 m s-1) and are insensitive towards friction (>360 N) and impact (10 J), having moderate to excellent thermal stability (171-262 °C). It is worth mentioning that the zwitterionic fused pyrazolo-triazole compound 2 and its energetic salts offer remarkable performance as new-generation thermally stable energetic materials.

Amphiphilic Molecules Exhibiting Zwitterionic Excited-State Intramolecular Proton Transfer and Near-Infrared Emission for the Detection of Amyloid β Aggregates in Alzheimer's Disease.

Chromophores with zwitterionic excited-state intramolecular proton transfer (ESIPT) have been shown to have larger Stock shifts and red-shifted emission wavelengths compared to the conventional π-delocalized ESIPT molecules. However, there is still a dearth of design strategies to expand the current library of zwitterionic ESIPT compounds. Herein, a novel zwitterionic excited-state intramolecular proton transfer system is reported, enabled by addition of 1,4,7-triazacyclononane (TACN) fragments on a dicyanomethylene-4H-pyran (DCM) scaffold. The solvent-dependent steady-state photophysical studies, pKa measurements, and computational analysis strongly support that the ESIPT process is more efficient with two TACN groups attached to the DCM scaffold and not affected by polar protic solvents. Impressively, compound DCM-OH-2-DT exhibits a near-infrared (NIR) emission at 740 nm along with an uncommonly large Stokes shift. Moreover, DCM-OH-2-DT shows high affinity towards soluble amyloid β (Aβ) oligomers in vitro and in 5xFAD mouse brain sections, and we have successfully applied DCM-OH-2-DT for the in vivo imaging of Aβ aggregates and demonstrated its potential use as an early diagnostic agent for AD. Overall, this study can provide a general molecular design strategy for developing new zwitterionic ESIPT compounds with NIR emission in vivo imaging applications.