Emergency care drugs' chemical stability after eight weeks' deployment in the prehospital setting.

Temperature conditions vary in emergency service vehicles, which may pose a risk to the integrity of the drugs on board, possibly rendering them ineffective and increasing morbidity and mortality in patients. Aim: This study assessed the stability of four emergency care drugs (adrenaline, etomidate, ketamine, and rocuronium) after eight weeks of deployment in the prehospital context. Methods: The study adopted a longitudinal quantitative design to evaluate the chemical stability of emergency care drugs. The study was conducted at four emergency medical service bases in Ballito, Durban and Pietermaritzburg, South Africa. The primary outcome was the relative reduction in drug concentration from the labelled concentration after four and eight weeks. High-performance liquid chromatography-mass spectrometry (HPLC-MS) analysed samples to determine the concentration of active ingredients in the drug samples. Results: HPLC analysis was done on 176 samples. The ambient temperature ranged from 18.7 to 44 °C in the first four weeks, averaging 26.8 °C ± 3.0. At 4 and 8 weeks, Adrenaline decreased 24.93 % and 22.73 %, respectively. Etomidate's control had 3.06 mg/ml, not the 2 mg/ml on the bottle. After 4 and 8 weeks, the samples had 3.10 and 3.15 mg/ml active components, respectively. Ketamine degraded over 30 % after four weeks but not beyond that. The Ketamine package states 10 mg/ml. However, we found 17.46 mg/ml. Rocuronium was 6.45 mg/ml in the control, although the manufacturer specified 10 mg/ml. At four weeks, the concentration was 6.70 mg/ml; at eight weeks, 6.56. Conclusion: This study suggests that adrenaline and ketamine degrade by more than 20 % within four weeks of deployment in the prehospital field, whereas etomidate and rocuronium remain stable after eight weeks.

The Effect of Conformational Freedom vs Restriction on the Rate in Asymmetric Hydrogenation: Iridium-Catalyzed Regio- and Enantioselective Monohydrogenation of Dienones.

Transition metal-catalyzed asymmetric hydrogenation constitutes an efficient strategy for the preparation of chiral molecules. When dienes are subjected to hydrogenation, control over regioselectivity still presents a large challenge and the fully saturated alkane is often yielded. A few successful monohydrogenations of dienes have been reported, but hitherto these are only efficient for dienes comprised of two distinctly different olefins. Herein, the reactivity of a conjugated carbonyl compound as a function of their conformational freedom is studied, based on a combined experimental and theoretical approach. It was found that alkenes in the (s)-cis conformation experience a large rate acceleration while (s)-trans restrained alkenes undergo hydrogenation slowly. Ultimately, this reactivity aspect was exploited in a novel method for the monohydrogenation of dienes based on conformational restriction ((s)-cis vs (s)-trans). This mode of discrimination conceptually differs from existing monohydrogenations and dienones constructed of two olefins similar in nature could efficiently be hydrogenated to the chiral alkene (up to 99 % ee). The extent of regioselection is even powerful enough to overcome the conventional reactivity order of substituted olefins (di>tri>tetra). This high yielding and atom-economical protocol provides an interesting opportunity to instal a stereogenic center on a carbocycle, while leaving a synthetically useful alkene untouched.

Synthesis, characterization, in vitro antimycobacterial and cytotoxicity evaluation, DFT calculations, molecular docking and ADME studies of new isomeric benzimidazole-1,2,3-triazole-quinoline hybrid mixtures.

New benzimidazole-1,2,3-triazole-quinoline hybrids and their intermediates, differing in substitutions at the C-2 and/or C6 positions of the benzimidazole ring, were successfully synthesized in 55---80 % yields, with the C6-substituted ones forming as inseparable tautomeric mixtures. The synthesized compounds were fully characterised by FT-IR, 1D- and 2D-NMR, and HRMS. In-depth NMR analysis and DFT molecular calculations showed that the tautomeric mixtures formed in a ratio of almost 1:1 ratio (cis and trans), except for 5 g, where the ratio is 1:2. In vitro antimycobacterial activity evaluation against the H37Rv strain of Mycobacterial tuberculosis was undertaken on all synthesized compounds, and a selected number were further screened for their cytotoxicity on TZM-bl cell lines. Hybrid compounds showed excellent MIC90 activities ranging from 1.07 to 8.66 µM and were all more efficacious than the first-line reference drug, ethambutol (MIC90 = 9.54 µM). In particular, hybrid compounds 5b (MIC90 = 1.54 µM, CC50 = 58.89 µM and % cell viability = 14.07), 5d (MIC90 = 2.08 µM, CC50 = 0.27 µM, and % cell viability = 149.50 %) and 5 g (MIC90 = 1.49 µM, CC50 = 4.62 µM and % cell viability = 44.03) were the most promising. Significantly, 5b and 5 g were over six times more efficacious than ethambutol but exhibited cytotoxicity towards TZM-bl cell-lines compared to 5d, which was over four times more active than ethambutol. The physical combination (mimicking combination therapy) of individual pharmacophoric components making up 5 g were less active, indicating the synergistic effect of hybridization. In addition, more than 60 % of all the synthesized hybrids showed better activity than their respective pharmacophoric components. In silico ADME studies of the hybrids revealed favourable physico-chemical properties, while molecular modeling studies suggested binding interactions with Val 61, Gly 62, Glu 65, Ala 66, and Phe 69 amino acid in a reported similar manner to bedaquiline, an approved quinoline-based anti-TB drug.

Structure-Activity Relationship and Molecular Docking of Quinazolinones Inhibiting Expression of COX-2, IL-1ß, iNOS, and TNF-α through NF-κB Pathways.

The quinazolinone scaffold is found in natural products and biologically active compounds, including inflammatory inhibitors. Major proteins or enzymes involved in the inflammation process are regulated by the amount of gene expression. Quinazolinone derivatives were investigated and developed against the inflammatory genes cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) in the lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cell line. The mRNA expressions were measured using a real-time quantitative polymerase chain reaction (RT-qPCR). Quinazolinone compounds at 62.5 µM demonstrated anti-COX-2 and anti-IL-1ß mRNA expressions down to 0.50% and 3.10% gene expression, respectively, via inhibition of nuclear factor κB (NF-κB). Molecular docking was performed to explain the interaction between the binding site and the developed compounds as well as the structure-activity relationship of the quinazolinone moiety.

Microwave-assisted commercial copper-catalyzed aerobic oxidative synthesis of AChE quinazolinone inhibitors under solvent free conditions.

A facile and green one-pot synthesis of AChE quinazolinone inhibitors was developed using microwave irradiation under solvent free conditions. Quinazolinones were synthesized from 2-aminobenzamide derivatives and various alcohols such as benzyl alcohol derivatives and butanol using economical commercially available copper as a catalyst in the presence of base, Cs2CO3. The desired products were achieved in moderate to high yields with up to 92% isolated yield. These quinazolinone products were then evaluated for acetylcholinesterase inhibition so that they can be developed as promising anti-acetylcholinesterase agents.

Iridium-Catalyzed Double Convergent 1,3-Rearrangement/Hydrogenation of Allylic Alcohols.

Enantioconvergent catalysis has the potential to convert different isomers of a starting material to a single highly enantioenriched product. Here we report a novel enantioselective double convergent 1,3-rearrangement/hydrogenation of allylic alcohols using an Ir-N,P catalyst. A variety of allylic alcohols, each consisting of a 1:1:1:1 mixture of four isomers, were converted to the corresponding tertiary alcohols with two contiguous stereogenic centers, in up to 99% ee and 99:1 d.r. DFT calculations, and control experiments suggest that the 1,3-rearrangement is the crucial stereodetermining element of the reaction.

Iridium-catalyzed enantioconvergent hydrogenation of trisubstituted olefins.

Asymmetric hydrogenation of olefins constitutes a practical and efficient method to introduce chirality into prochiral substrates. However, the absolute majority of the developed methodologies is enantiodivergent and thus require isomerically pure olefins which is a considerable drawback since most olefination strategies produce (E/Z)-mixtures. Although some advances have been reported, a general enantioconvergent hydrogenation featuring a broad functional group tolerance remains elusive. Here, we report the development of a general iridium-catalyzed enantioconvergent hydrogenation of a broad range of functionalized trisubstituted olefins. The substitution pattern around the olefin is critical; whereas α-prochiral olefins can undergo an enantioconvergent hydrogenation, ß-prochiral olefins react in an enantiodivergent manner. The presented methodology hydrogenates α-prochiral substrates with excellent control of enantioselection and high isolated yields. Most importantly, both isomerically pure alkenes as well as isomeric mixtures can be hydrogenated to yield the same major enantiomer in excellent enantiomeric excesses which is unusual in transition-metal catalyzed asymmetric hydrogenations.

A Review on Interactions between Amino Acids and Surfactants as Well as Their Impact on Corrosion Inhibition.

Amino acid-surfactant interactions are central to numerous studies because of their increased effectiveness in chemical, biological, household and industrial use. This review will focus on the impact and effect of the physicochemical properties, temperature, pH, and surfactant chain length of the amino acid for detailed exploration of amino acids and surfactants in aqueous medium. The impact of cosolvent on self-aggregation, critical micelle concentration (CMC), and binding affinity with other biomolecules, as well as amino acid-surfactant interactions, are the epicenters. The results show that increasing the temperature causes negative enthalpy for ionic surfactants and micellization, implying that micellization and amino acids are thermodynamically spontaneous and exothermic, accompanied by positive entropy. As these physicochemical studies are additive, the amino acid and ionic surfactant interactions provide clues on protein unfolding and denaturation under different media, which further changes with a change in physiological conditions like pH, cosolvent, chain length, and temperature. On varying the pH, the net charge of the amino acid also changes and, subsequently, the binding efficiency of the amino acids to the surfactants. The presence of cosolvent causes a lowering in the hydrophobic chain, which changes the surfactant's CMC. At a reduced CMC, the hydrophobic characteristic of amino acid-surfactant associations is amplified, leading to rapid denaturation of proteins that act as propulsion under the influence of extended chain surfactants. Amino acids are one of the most intriguing classes of chemicals that produce high inhibitory efficacy. Amino acids are also a component of proteins and therefore, found in a significant part of the human body, further making them a promising candidate as corrosion inhibitors. In this review article, authors have also focused on the collection and investigation for application of amino acid-surfactant interactions in corrosion inhibition. Various predictive studies/in silico studies are also reported by many research groups, such as density functional theory (DFT) calculations and molecular dynamics simulations to obtain tentative electronic, structural, and physiochemical characteristics like energies of the highest occupied molecular orbitals and lowest unoccupied molecular orbitals, binding energy, Gibb's free energy, electronegativity, polarizability, and entropy. In silico studies are helpful for the mechanism predictions of the process occurring on metal surfaces.

Combined Theoretical and Experimental Studies Unravel Multiple Pathways to Convergent Asymmetric Hydrogenation of Enamides.

We present a highly efficient convergent asymmetric hydrogenation of E/Z mixtures of enamides catalyzed by N,P-iridium complexes supported by mechanistic studies. It was found that reduction of the olefinic isomers (E and Z geometries) produces chiral amides with the same absolute configuration (enantioconvergent hydrogenation). This allowed the hydrogenation of a wide range of E/Z mixtures of trisubstituted enamides with excellent enantioselectivity (up to 99% ee). A detailed mechanistic study using deuterium labeling and kinetic experiments revealed two different pathways for the observed enantioconvergence. For α-aryl enamides, fast isomerization of the double bond takes place, and the overall process results in kinetic resolution of the two isomers. For α-alkyl enamides, no double bond isomerization is detected, and competition experiments suggested that substrate chelation is responsible for the enantioconvergent stereochemical outcome. DFT calculations were performed to predict the correct absolute configuration of the products and strengthen the proposed mechanism of the iridium-catalyzed isomerization pathway.

Site- and Enantioselective Iridium-Catalyzed Desymmetric Mono-Hydrogenation of 1,4-Dienes.

The control of site selectivity in asymmetric mono-hydrogenation of dienes or polyenes remains largely underdeveloped. Herein, we present a highly efficient desymmetrization of 1,4-dienes via iridium-catalyzed site- and enantioselective hydrogenation. This methodology demonstrates the first iridium-catalyzed hydrogenative desymmetriation of meso dienes and provides a concise approach to the installation of two vicinal stereogenic centers adjacent to an alkene. High isolated yields (up to 96 %) and excellent diastereo- and enantioselectivities (up to 99:1 d.r. and 99 % ee) were obtained for a series of divinyl carbinol and divinyl carbinamide substrates. DFT calculations reveal that an interaction between the hydroxy oxygen and the reacting hydride is responsible for the stereoselectivity of the desymmetrization of the divinyl carbinol. Based on the calculated energy profiles, a model that simulates product distribution over time was applied to show an intuitive kinetics of this process. The usefulness of the methodology was demonstrated by the synthesis of the key intermediates of natural products zaragozic acid A and (+)-invictolide.

Exploring the bioactivity of pentacyclic triterpenoids as potential antimycobacterial nutraceutics: Insights through comparative biomolecular modelling.

A group of bioactive compounds known as triterpenoids, which are often found in plant materials, have been tested to possess nutritional and pharmaceutical activity. These plant components are referred to as nutraceuticals, and are used as therapeutic agents. In this study, we explore the interactions of betulinic acid (BA), oleanolic acid (OA), ursolic acid (UA), and maslinic acid (MA) against FadA5. Studies have identified FadA5, a trifunctional enzyme-like thiolase, as a target towards Mycobacterium tuberculosis inhibition. The investigation involves molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) applications. Analyses of the four pentacyclic triterpenoids binding to FadA5 showed appreciable bioactivity against FadA5. The application of two or more theoretical models to unravel ligand-enzyme binding energies can pave the way for accurate binding affinity prediction and validation.

Green Synthesis, Experimental and Theoretical Studies to Discover Novel Binders of Exosomal Tetraspanin CD81 Protein.

A new class of benzothiazole-appended quinoline derivatives (6-8) was synthesized via one-pot TPGS micellar-mediated acid-catalyzed nucleophilic addition, followed by aerobic oxidative cyclization of 3-formylquinoline-2-one (2), 3-formylquinoline-2-thione (3), and 2-azidoquinoline-3-carbaldehyde (4) individually with 2-amino thiophenol (5). The structures of the prepared compounds were confirmed using suitable spectroscopic methods complemented with single-crystal X-ray diffraction analysis. Time-dependent density functional theory-based optimization of molecular structures, bond lengths, bond angles, HOMO-LUMO energy gaps, and molecular electrostatic potential maps was theoretically computed at the B3LYP/6-311++g(d) level. The molecular docking studies recommended that 6-8 bound to the active site cavity of CD81 effectively with the binding energies of -6.9, -6.3, and -6.5 kcal mol-1, respectively. Further, MD simulation studies of compound 6 suggested that the binding resulted in the stabilization of the CD81 molecule. Thus, all theoretical predictions associated with the experimental verifications motivated to discover novel approaches for cancer therapy.

Selenium-Directed ortho-C-H Borylation by Iridium Catalysis.

An iridium-catalyzed selenium-directed ortho-C-H borylation of benzyl selenide derivatives was successfully developed. This is the first example where selenium is used as a directing group in C-H borylation. The reaction was carried out using the tricyclohexylphosphine ligand for an improved catalytic efficiency. Various substrates were tolerated and afforded either ortho-monoborylated products (substrates bearing ortho- or meta-substituents) or diborylated products (substrates bearing para-substituents) in good yields. This study provides an efficient synthetic method for the preparation of a variety of organoselenium compounds.

Kinetic resolution of racemic allylic alcohols via iridium-catalyzed asymmetric hydrogenation: scope, synthetic applications and insight into the origin of selectivity.

Asymmetric hydrogenation is one of the most commonly used tools in organic synthesis, whereas, kinetic resolution via asymmetric hydrogenation is less developed. Herein, we describe the first iridium catalyzed kinetic resolution of a wide range of trisubstituted secondary and tertiary allylic alcohols. Large selectivity factors were observed in most cases (s up to 211), providing the unreacted starting materials in good yield with high levels of enantiopurity (ee up to >99%). The utility of this method is highlighted in the enantioselective formal synthesis of some bioactive natural products including pumiliotoxin A, inthomycin A and B. DFT studies and a selectivity model concerning the origin of selectivity are presented.

Stereodivergent Synthesis of Trisubstituted Enamides: Direct Access to Both Pure Geometrical Isomers.

A stereodivergent strategy has been developed to access either (E)- or (Z)-isomers of trisubstituted enamides. Starting from an extensive range of ketones, it was possible to synthesize and isolate the desired pure isomer by switching the reaction conditions. Lewis acid activation enables the formation of the (E)-isomers in high stereoselectivity (>90:10) and good yields. On the other hand, the use of a Brønsted acid allows the preparation of the (Z)-isomers, again in high selectivity (up to 99:1), with moderate yields.

Tandem Peterson olefination and chemoselective asymmetric hydrogenation of ß-hydroxy silanes.

Here, we report the first Ir-N,P complex catalyzed tandem Peterson olefination and asymmetric hydrogenation of ß-hydroxy silanes. This reaction resulted in the formation of chiral alkanes in high isolated yields (up to 99%) and excellent enantioselectivity (up to 99% ee) under mild conditions. Modification of the reaction conditions provides a choice to transform either an olefin or the ß-hydroxy silane in a chemoselective manner. Additionally, based on this method, an expedient enantioselective synthesis of (S)-(+)-α-curcumene, from a simple ketone, was accomplished in two steps with 75% overall yield and 95% ee.

Regioselective Iridium-Catalyzed Asymmetric Monohydrogenation of 1,4-Dienes.

A highly efficient regio- and enantioselective monohydrogenation of 1,4-dienes has been realized using an iridium catalyst with a chiral N,P-ligand under mild conditions. The substrate scope was studied and included both unfunctionalized as well as functionalized substituents on the meta- or para-position. Substrates having substituents with functionalities such as silyl protected alcohols or ketals were monohydrogenated in high regioselectivity and high enantiomeric excess (up to 98% ee).

Biosynthesis and computational analysis of amine-ended dual thiol ligand functionalized gold nanoparticles for conventional spectroscopy detection of melamine.

The bio-synthesized DTAuNPs have an average size of 21nm. The aggregation extent depends on the concentration of melamine, which was validated by UV-vis spectra and visual method of melamine detection was developed. The major observation in this method was the color change of DTAuNPs from red to purple due to the aggregation of ligand capped gold nanoparticles instigated by melamine. The reaction of color changes were processed due to the shifting of bonding in hydrogen in between nanoparticles and melamine. The aggregation extent depends on the concentration of melamine, which can be validated UV-vis spectra and visual method of detecting melamine is developed. The electron density and conventional UV-vis, FTIR spectroscopy and DFT studies on the ligand was performed using computational methods. The theoretical and experimental data for the energy transitions and the molar extinction coefficients of the ligands studied has been obtained. Further, the ligand capped gold nanoparticles was assessed for cytotoxicity against A549 cells which resulted in significant decrease in cell viability was noted in 50µg/mL DTAu, 4-ATP and AXT treated cells at 2h (85% and 66%) and 6h (83% and 36%) respectively, (p<0.01) were studied and reported in this manuscript.

Experimental and theoretical mechanistic investigation of the iridium-catalyzed dehydrogenative decarbonylation of primary alcohols.

The mechanism for the iridium-BINAP catalyzed dehydrogenative decarbonylation of primary alcohols with the liberation of molecular hydrogen and carbon monoxide was studied experimentally and computationally. The reaction takes place by tandem catalysis through two catalytic cycles involving dehydrogenation of the alcohol and decarbonylation of the resulting aldehyde. The square planar complex IrCl(CO)(rac-BINAP) was isolated from the reaction between [Ir(cod)Cl]2, rac-BINAP, and benzyl alcohol. The complex was catalytically active and applied in the study of the individual steps in the catalytic cycles. One carbon monoxide ligand was shown to remain coordinated to iridium throughout the reaction, and release of carbon monoxide was suggested to occur from a dicarbonyl complex. IrH2Cl(CO)(rac-BINAP) was also synthesized and detected in the dehydrogenation of benzyl alcohol. In the same experiment, IrHCl2(CO)(rac-BINAP) was detected from the release of HCl in the dehydrogenation and subsequent reaction with IrCl(CO)(rac-BINAP). This indicated a substitution of chloride with the alcohol to form a square planar iridium alkoxo complex that could undergo a ß-hydride elimination. A KIE of 1.0 was determined for the decarbonylation and 1.42 for the overall reaction. Electron rich benzyl alcohols were converted faster than electron poor alcohols, but no electronic effect was found when comparing aldehydes of different electronic character. The lack of electronic and kinetic isotope effects implies a rate-determining phosphine dissociation for the decarbonylation of aldehydes.