Abstract Naloxone, naltrexone and nalmefene are closely related morphinan antagonists with comparable affinities to the μ-opioid receptor (MOR) but markedly different pharmacokinetics (PK) and metabolic fate. In this study, we evaluated their pharmacologically-relevant molecular/physicochemical properties, PAMPA-BBB (Parallel Artificial Membrane Permeability Assay for the Blood-Brain Barrier) permeability and in vitro metabolic stability to determine how subtle structural differences influence ADME-relevant properties. Moreover, the pharmacologically-relevant properties of these three antagonists were compared with those of the best-known synthetic opioid agonist, fentanyl. We found that the methyl-cyclopropyl versus allyl head group, as well as the C6-carbonyl versus C6-ethenyl group, dramatically influence all the above-mentioned properties and help explain the in vivo observed differences between these antagonists. These results may support the rational design of new and improved opioid antagonists with optimized PK properties.

The chemical shift of the NH+ proton of protonated amines (δ(NH+)) may be influenced by both the H-bond basicity of the counteranion (pKBHX) and by the pKa value of the amine, depending on the conditions used for the 1H NMR spectroscopy. In the present study, we found an excellent pKBHX-δ(NH+) correlation in various tertiary ammonium salts (RR1R2NH+ X-, CDCl3). Moreover, from a complementary standpoint, we also found an excellent amine pKa-δ(NH+) correlation, for each counteranion separately, provided that no charge-assisted intramolecular H-bond (CA-IMHB) occurs. Thus, we show that in a simple single 1H NMR measurement of a given tertiary ammonium salt in CDCl3, focusing on the δ(NH+) value, one obtains reliable prediction of the amine aqueous pKa value, the counteranion pKBHX, or even an assessment of possible CA-IMHBs between the protonated amine and a nearby hydrogen bond acceptor group.

Novichoks are highly toxic chemical warfare agents (CWAs), which gained significant attention after being used in the assassination attempt of Sergei Skripal (2018, Salisbury). Since then, only a limited number of experimental studies on Novichoks were conducted with focus on their physicochemical properties, toxicology and pharmacology. Their stability on various matrices has received even minor consideration. Herein, we present a comprehensive study on the fate of A232, a prominent Novichok agent, on a variety of previously unexamined environmental and urban matrices, using solid and solution state 31P NMR techniques. The matrices studied included limestone soil, desert soil, silicate sand, asphalt, fresh and old concrete and sawdust, all in dry and wet forms. A232 was found to be highly persistent on most matrices, with degradation being very slow or nonexistent. Once degradation occurred, its products stemmed from either a PN bond or a PF bond cleavage or double hydrolysis of both leaving groups, depending on the matrix. The results indicate that A232 poses significant, long-term threat to the environment across a diverse range of realistic scenarios. Importantly, A232 adsorbed on solid support was rapidly and completely hydrolyzed to a nontoxic product once treated with only a few equivalents of NaOH.

Increasing the molecular rigidity of bioactive compounds by intramolecular hydrogen bonds (IMHB) may affect both pharmacodynamics (PD) and pharmacokinetics (PK) by an increase in molecular recognition, lipophilicity and membrane permeability. Recently, in our study on opioids lipophilicity, we suggested two types of IMHBs, i.e., O-H⋯N and N+-H…O, which may exist in 14-oxymorphinan structures and may explain some trends and even apparent anomalies in their pharmacologically relevant molecular properties. In the present study we show, both experimentally and computationally, that these IMHBs indeed exist in the three FDA-approved opioid antagonists, Naloxone, Naltrexone and Nalmefene, as well as in their 3-O- and 14-O-methylated derivatives. Since the charged form of these morphinans is the biologically active species, we propose that the charge-assisted IMHB (CAHB) N+-H…O, which is herein studied for the first time, plays an important role in the bioactivity of this subfamily of opioids.

There is an urgent need today for interface management with recognition layers composed of short receptor molecules, with excellent specificity and affinity toward a target molecule, for a wide range of sensing applications. The current work demonstrates a specific detection of a G-type nerve agent, which is based on a nucleophilic substitution reaction between the surface-bound 4-amino-2-((dimethylamino)methyl)phenol (amino-2-DMAMP) receptors and the diethyl chlorophosphate (DCP) simulant. The specificity and affinity of 2-DMAMP toward DCP are demonstrated with 31P-nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI-MS/MS). The specificity of the proposed recognition layer is utilized and demonstrated through the design and realization of an electronic chemosensor using the meta-nanochannel field-effect transistor (MNC FET). The SiO2 sensing area of the MNC FET is functionalized with amino-2-DMAMP receptors using amine-based chemistry, and the response toward DCP is quantified. An excellent specificity is demonstrated, coupled with a limit of detection of 1 pg/mL, a dynamic range of 8 orders of magnitude, and excellent linearity and sensitivity. The high specificity and affinity of the recognition layer coupled with the high electronic grade of the MNC FET pave the way to specific, label-free, quantitative, low-cost, easy-to-operate, and field-deployable sensors.

Activated carbon filters are used for the removal of hazardous gases from the air. This research applied vibrational spectroscopy methods, including Fourier-transform infrared spectroscopy and Raman spectroscopy to characterize hydrogen sulfide adsorption on impregnated carbon materials with metals having reactivity toward hydrogen sulfide. The Fourier-transform infrared spectroscopy results demonstrated the formation of a new chemical bond between the impregnating metals and the sulfur, indicated by the appearance of a new band at 618 cm-1. The Raman spectra results showed that for the copper-impregnated activated carbon with the highest hydrogen sulfide adsorption capacity, a new vibrational band at 475 cm(-1) evolved, indicating a copper-sulfur bond. In addition, upshifts in the carbon D sub-bands were observed after efficient hydrogen sulfide adsorption, along with a larger area of the approximately 1500 cm(-1) band. Therefore, Fourier-transform infrared spectroscopy and Raman spectroscopy combination can potentially indicate H2S adsorption on impregnated activated carbon filters.

Highly sensitive chemiluminescence-based probes that effectively detect and differentiate between the extremely toxic real G- and V-type organophosphorus chemical warfare agents (OPCWAs) are presented. This straightforward approach does not require any instrumentation or light source; hence, it appears ideal for the future development of field colorimetric detectors. Highly sensitive chemiluminescence-based probes that effectively detect and differentiate between the extremely toxic real G- and V-type organophosphorus chemical warfare agents (OPCWAs) are presented.

Fluorine atoms play an important role in all branches of chemistry and accordingly, it is very important to study their unique and varied effects systematically, in particular, the structure-physicochemical properties relationship. The present study describes exceptional physicochemical effects resulting from a H/F exchange at the methylene bridge of gem-difunctional compounds. The Delta log P(CF2-CH2) values, that is, the change in lipophilicity, observed for the CH2/CF2 replacement in various alpha,alpha-phenoxy- and thiophenoxy-esters/amides, diketones, benzodioxoles and more, fall in the range of 0.6-1.4 units, which for most cases, is far above the values expected for such a replacement. Moreover, for compounds holding more than one such gem-difunctional moiety, the effect is nearly additive, so one can switch from a hydrophilic compound to a lipophilic one in a limited number of H/F exchanges. DFT studies of some of these systems revealed that polarity, conformational preference as well as charge distributions are strongly affected by such hydrogen to fluorine atom substitution. The pronounced effects described, are a result of the interplay between changes in polarity, H-bond basicity and molecular volume, which were obtained with a very low 'cost' in terms of molecular weight or steric effects and may have a great potential for implementation in various fields of chemical sciences.

Impregnated activated carbons (IACs) used in air filtration gradually lose their efficacy for the chemisorption of noxious gases when exposed to humidity due to impregnated metal deactivation. In order to stabilize IACs against aging, and to prolong the filters' shelf life, inorganic phosphate compounds (phosphoric acid and its three salts, NaHPO4, Na2HPO4, and Na3PO4) were used as anti-aging additives for two different chromium-free IACs impregnated with copper, zinc, molybdenum, and triethylenediamine (TEDA). Phosphoric acid, monosodium, and disodium phosphate were found to be very efficient in inhibiting the aging of IACs over long periods against cyanogen chloride (the test agent) chemisorption, with the latter being the most efficient. However, the efficiency of phosphate as an anti-aging additive was not well correlated with its ability to inhibit the migration of metal impregnants, especially copper, from the interior to the external surface of carbon granules. Unlike organic additives, the inorganic phosphate additives did not decrease the surface area of the IAC or its physical adsorption capacity for toluene. Using a phosphate additive in IAC used in collective protection and personal filters can improve the safety of the user and the environment and dramatically reduce the need to replace these filters after exposure to humid environments. This has safety, economic, logistical, and environmental advantages.

A novel self-decontaminating protective barrier was developed for in situ catalytic and photocatalytic degradation of the chemical warfare agent sarin. A polymeric matrix comprising a polydimethylsiloxane (PDMS) sheet embedded with TiO2 nanoparticles (4-10 nm) supported on mesoporous silica (SBA-15) was used to create the novel reactive barrier. The catalysts/photocatalysts were synthesized in two ways: on the silica surface and within the silica matrix. These two catalysts differed in their structural, textural, and spectroscopic properties and formed different active sites that affected their catalytic and photocatalytic activities. Combining the two synthesis methods yielded a highly effective self-decontamination PDMS composite barrier. After 6 h, 87% of the adsorbed sarin in the hybrid matrix was decomposed: 72% by the photocatalysis mechanism and 15% by the catalyzed hydrolysis (dark) mechanism. This study demonstrates the potential of TiO2/SBA-15 to impart reactive properties to an inert polymeric barrier, enhancing its protective capabilities and minimizing the potential environmental risk from hazardous materials.

Chemical analysis of hazardous surface contaminations, such as hazardous substances, explosives or illicit drugs, is an essential task in security, environmental and safety applications. This task is mostly based on the collection of particles with swabs, followed by thermal desorption into a vapor analyzer, usually a detector based on ion mobility spectrometry (IMS). While this methodology is well established for several civil applications, such as border control, it is still not efficient enough for various conditions, as in sampling rough and porous surfaces. Additionally, the process of thermal desorption is energetically inefficient, requires bulky hardware and introduces device contamination memory effects. Low-temperature plasma (LTP) has been demonstrated as an ionization and desorption source for sample preparation-free analysis, mostly at the inlet of a mass spectrometer analyzer, and in rare cases in conjunction with an ion mobility spectrometer. Herein, we demonstrate, for the first time, the operation of a simple, low cost, home-built LTP apparatus for desorbing non-volatile analytes from various porous surfaces into the inlet of a handheld IMS vapor analyzer. We show ion mobility spectra that originate from operating the LTP jet on porous surfaces such as asphalt and shoes, contaminated with model amine-containing organic compounds. The spectra are in good correlation with spectra measured for thermally desorbed species. We verify through LC-MS analysis of the collected vapors that the sampled species are not fragmented, and can thus be identified by commercial IMS detectors.

In this study, a reactive adsorbent filler was integrated into a polymeric matrix as a novel reactive protective barrier without undermining its mechanical, thermal, and chemical properties. For this purpose, newly synthesized TiO2/MCM/polydimethylsiloxane (PDMS) composites were prepared, and their various properties were thoroughly studied. The filler, TiO2/MCM, is based on a (45 wt%) TiO2 nanoparticle catalyst inside the pores of ordered mesoporous silica, MCM-41, which combines a high adsorption capacity and catalytic capability. This study shows that the incorporation of TiO2/MCM significantly enhances the composite's Young's modulus in terms of tensile strength, as an optimal measurement of 1.6 MPa was obtained, compared with that of 0.8 MPa of pristine PDMS. The composites also showed a higher thermal stability, a reduction in the coefficient of thermal expansion (from 290 to 110 ppm/°C), a 25% reduction in the change in the normalized specific heat capacity, and an increase in the thermal degradation temperatures. The chemical stability in organic environments was improved, as toluene swelling decreased by 40% and the contact angle increased by ~15°. The enhanced properties of the novel synthesized TiO2/MCM/PDMS composite can be used in various applications where a high adsorption capacity and catalytic/photocatalytic activity are required, such as in protective equipment, microfluidic applications, and chemical sensor devices.

Systematically studying the lipophilicity of phosphorus compounds is of great importance for many chemical and biological fields and particularly for medicinal chemistry. Here, we report on the study of trends in the lipophilicity of a wide set of phosphorus compounds relevant to drug design including phosphates, thiophosphates, phosphonates, thiophosphonates, bis-phosphonates, and phosphine chalcogenides. This was enabled by the development of a straightforward log P determination method for phosphorus compounds based on 31P-NMR spectroscopy. The log P values measured ranged between -3.2 and 3.6, and the trends observed were interpreted using a DFT study of the dipole moments and by H-bond basicity (pKHB) measurements of selected compounds. Clear signal separation in 31P-NMR spectroscopy grants the method high tolerability to impurities. Moreover, the wide range of chemical shifts for the phosphorus nucleus (250 to -250 ppm) enables a direct simultaneous log P determination of phosphorus compound mixtures in a single shake-flask experiment and 31P-NMR analysis.

Three DBA derivatives containing different electron donor and acceptor units display both ICT and AIE properties. The intriguing optical features of the molecules have been employed for selective, high sensitivity detection of organophosphate vapors.

Activated carbon is typically being used as an adsorbent material for various hazardous materials. It is common to impregnate the carbon with metal oxides in order to improve its adsorbing capabilities to polar hydrophilic compounds. Exposure of activated carbon to humidity causes water adsorption that leads to aging of the carbon. The aging process reduces the chemisorption capacity of the activated carbon, thus deteriorating its adsorption properties. In this research, the effect of aging on activated carbon was studied by non-destructive Raman spectroscopy, which enables chemical characterization of packed AC samples. Accelerated aging was achieved by controlling thermal oxidation of carbonaceous materials. The aging process of the activated carbon which includes carbon oxidation, as well as metal ions migrations was studied using Raman spectroscopy utilizing mainly D and G Raman band shifts, as well as energy dispersive spectroscopy.

Low permeability and self-decontamination are extremely desired features for protective equipment against chemical warfare agents (CWAs). similar to 4nm TiO2 nanoparticles were synthesized in the porous matrix of MCM-41 (45 wt%) as a novel reactive adsorbent for the degradation of sarin and VX. TiO2 /MCM-41 (similar to 520 m(2)/g) was embedded in a polydimethylsiloxane (PDMS) sheet. PDMS was chosen as a model for an air-impermeable barrier with high permeability to CWAs. The incorporation of the reactive adsorbent decreased the diffusion coefficients, increased the breakthrough time, and dramatically decreased the desorption of sarin and VX vapors. The adsorbed CWAs in the hybrid matrix decompose (>= 99%) to the nontoxic corresponding acids after 1 and 3 days for VX and sarin, respectively. This study demonstrates, for the first time, the potential of TiO2/MCM-41 as a reactive adsorbent embedded in polymeric matrices to improve the protection level and safety of protective equipment via combined adsorption and self-decontamination.

Sampling hazardous compounds in the form of solids and liquids is a growing need in the fields of homeland security and forensics. Chemical analysis of particles and droplets under field conditions is crucial for various tasks carried out by counter-terrorism and law enforcement units. The use of simple, small and low cost means to achieve this goal is constantly pursued. In this work, an approach for rapid, continuous generation of vapors from liquid samples using sonic spray (SS) as the sample introduction technique, followed by analysis using hand-held ion mobility spectrometry (IMS) vapor analyzers is presented. Transfer of analytes is demonstrated from liquid state to the gas phase at the inlet of an IMS detector using a sonic spray apparatus that consists of a nebulizer, spraying solution, a source of compressed gas and an unheated transfer line tube to the detector inlet nozzle. This technique does not require any electrical, radiative or thermal energy. Analysis of several narcotic substances including cocaine, methamphetamine and amphetamine, and of an explosive compound, TNT, is demonstrated, using two commercial devices as analyzers. Two sampling configurations are presented: direct sampling of liquid, either from a vial or a spill (SS-IMS) and extraction of a substance collected with a swab by dipping it in the spray solvent (ESS-IMS), being suitable for both drops and particles. Limits of detection of the presented method are comparable to those obtained with thermal desorption sample introduction of the commercial device. Time traces of the IMS signals show a continuous and stable signal with a short rise time. This sampling technique may offer competitive performance to that of common thermal desorption techniques, with the advantages of coupling to simpler, smaller and cheaper vapor detectors, optimized for field use, and of a continuous, pulseless sample or object interrogation.

Modulation of the H-bond basicity (pKHB) of various functional groups (FGs) by attaching fluorine functions and its impact on lipophilicity and bioisosterism considerations are described. In general, H/F replacement at the α-position to H-bond acceptors leads to a decrease of the pKHB value, resulting, in many cases, in a dramatic increase in the compounds' lipophilicity (log Po/w). In the case of α-CF2H, we found that these properties may also be affected by intramolecular H-bonds between CF2H and the FG. A computational study of ketone and sulfone series revealed that α-fluorination can significantly affect overall polarity, charge distribution, and conformational preference. The unique case of α-di- and trifluoromethyl ketones, which exist in octanol/water phases as ketone, hemiketal, and gem-diol forms, in equilibrium, prevents direct log Po/w determination by conventional methods, and therefore, the specific log Po/w values of these species were determined directly, for the first time, using Linclau's 19F NMR-based method.

We developed and optimized surface-enhanced Raman spectrometry (SERS) methods for trace analysis of explosive vapour and particles using a hand-held Raman spectrometer in the field. At first, limits of detection (LODs) using SERS methods based on a colloidal suspension of gold nanoparticles were measured under alkaline conditions and are as follows: pentaerythritol tetranitrate (PETN) (1.5 × 10-6 M, 6.9 ng), 1,3,5,7-tetranitro-1,3,5,7-tetrazoctane (HMX), 8.1 × 10-6 M, 35 ng; urea nitrate (UN), 9.2 × 10-4 M, 165 ng; 2,4,6-trinitrotoluene (TNT), 1.1 × 10-7 M, 0.35 ng. We developed SERS substrates that demonstrate the wide applicability of this technique for use in the field for explosive vapour and particles adsorbed on a surface based on Au nanoparticles that were optimal for the detection of the target materials in solution. Au nanoparticles were modified onto quartz fibres or a polyurethane sponge for vapour/particles detection. SERS detection of vapours of 2,4-dinitrotoluene (2,4-DNT) and 1,3-dinitrobenzene (1,3-DNB) was shown by sampling vapours onto Au-modified quartz fibres followed by hand-held Raman analysis with estimated minimum detection levels of 3.6 ng and 54 ng, respectively. The detection of 2,4-DNT using sponge-based SERS decorated with Au nanoparticles was also demonstrated; however, the sensitivity was lower than that observed using quartz fibres. The detection of TNT on a surface was performed by utilizing quartz-fibres precoated with alumina and modified with Au nanoparticles, and the detection of 10 μg (0.53 μg cm-2) of TNT was demonstrated.

A novel SWIFT-based strategy for fluorimetric detection of practical amounts (minimal effective dose or lower) of chemical warfare agents is reported. This strategy employs readily available reagents and allows distinguishing between the V and G agents, as well as their discrimination from potential interferents.