Rapid discrimination of enantiomers by ion mobility mass spectrometry and chemical theoretical calculation: Chiral mandelic acid and its derivatives.

Because R/S-mandelic acids (MA) and their derivatives are critical starting materials or intermediates in the synthesis of chiral drugs, their chirality discrimination is important. In this study, R/S-MA and its derivatives, including R/S-2-phenylpropionic acid (2-PPA), R/S-methoxyphenylaceticacid (MPA), and R/S-2-hydroxy-4-phenylbutyric acid (HPBA), were accurate simultaneous mobility-discriminated by forming diastereomer complexes for the first time, which were obtained by simply mixing with cyclodextrins (α, ß, γ-CD) and transition-metal ions (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and Zn2+). The mass spectra revealed non-covalent diastereomer complexes formed by CD, enantiomers, and metal ions, and ion-mobility spectrometry (IMS) was performed for 109 pairs of complexes. Significant chiral discrimination was observed in the formed diastereomeric complexes, and their separation peak-to-peak resolution (Rp-p) for the enantiomers depended on the transition metal ion type. In most cases, the Rp-p value gradually increases with CD size, with quaternary complexes having the largest Rp-p value. The greatest chiral distinctions of 2-PPA, MA, MPA, and HPBA were obtained by the diastereomeric complex ions of [(2-PPA)(α)2+Zn2+-H]+, [(MA)(α)2+Zn2+-H]+, [(MPA)2(ß)+Co2+-H]+, and [(HPBA)(α)2+Fe2+-H]+, with Rp-p values of 1.35, 1.57, 1.70, and 0.71, respectively. Furthermore, the favorable conformation and collisional cross section (CCS) value of the different [CD + R/S-MA + Cu-H]+ complexes were measured using chemical theoretical calculations to detail their intermolecular interaction, revealing that [α-CD + R/S-MA + Cu-H]+ has two favored gas complexes, and the CCS calculated were consistent with the TIMS observed. In addition, R2 > 0.99 was obtained for the relative quantification of the chiral enantiomers. Overall, the proposed method provides a promising strategy for distinguishing the enantiomers of MA and their derivatives, with the advantages of simplicity, speed, and accuracy, without the need for complex chemical derivatization or chromatographic separation.

Enantioseparation of amino acid and mandelic acid enantiomers using Garphos derivatives as chiral extractants.

In this paper, Garphos with different substituents were employed as chiral extractants to enantioseparate racemic amino acid and mandelic acid. The influences of metal precursors, pH of aqueous solution, Garphos-metal concentration, extraction temperature, and substituent effect on extraction were investigated. The results indicated that the substituent groups significantly affected the π-π interaction between extractant and substrate. And the separation factors (α) for Garphos could be remarkably improved by regulating substituent groups. Garphos-II-Pd, Garphos-VI-Pd, Garphos-III-Pd, Garphos-I-Cu, Garphos-VI-Cu, and Garphos-V-Pd were the most efficient extractants for phenylalanine (Phe), homophenylalanine (Hphe), 4-nitrophenylalanine (Nphe), 3-chlorophenylglycine (Cpheg), mandelic acid (MA), and 2-chlormandelic acid (CMA) with α values of 2.40, 2.37, 5.37, 1.59, 5.98, and 3.69, respectively. This work provided an important reference for the design of efficient chiral extractants in future work.

Bacterial mandelic acid degradation pathway and its application in biotechnology.

Mandelic acid and its derivatives are an important class of chemical synthetic blocks, which is widely used in drug synthesis and stereochemistry research. In nature, mandelic acid degradation pathway has been widely identified and analysed as a representative pathway of aromatic compounds degradation. The most studied mandelic acid degradation pathway from Pseudomonas putida consists of mandelate racemase, S-mandelate dehydrogenase, benzoylformate decarboxylase, benzaldehyde dehydrogenase and downstream benzoic acid degradation pathways. Because of the ability to catalyse various reactions of aromatic substrates, pathway enzymes have been widely used in biocatalysis, kinetic resolution, chiral compounds synthesis or construction of new metabolic pathways. In this paper, the physiological significance and the existing range of the mandelic acid degradation pathway were introduced first. Then each of the enzymes in the pathway is reviewed one by one, including the researches on enzymatic properties and the applications in biotechnology as well as efforts that have been made to modify the substrate specificity or improving catalytic activity by enzyme engineering to adapt different applications. The composition of the important metabolic pathway of bacterial mandelic acid degradation pathway as well as the researches and applications of pathway enzymes is summarized in this review for the first time.

Constitutive secretory expression and characterization of nitrilase from Alcaligenes faecalis in Pichia pastoris for production of R-mandelic acid.

Nitrilases can directly hydrolyze nitrile compounds into carboxylic acids and ammonium. To solve the current problems of bioconversions using nitrilases, including the difficult separation of products from the resting cells used as the catalyst and high costs of chemical inducers, a nitrilase from Alcaligenes faecalis was heterologously expressed in Pichia pastoris X33. The stable nitrilase-expressing strain No.39-6-4 was obtained after three rounds of screening based on a combined detection method including dot-blot, SDS-PAGE, and western blot analyses, which confirmed the presence of recombinant nitrilase with a molecular mass of about 50 kDa. The temperature and pH optima of the nitrilase were 45°C and pH 7.5, respectively. Cu2+ , Zn2+ , and Tween 80 strongly inhibited the enzyme activity, but the optical purity of the product R-mandelic acid (R-MA) was stable, with practically 100% enantiomeric excess (ee). The nitrilase-producing P. pastoris strain developed in this study provides a basis for further research on the enzyme.

Resolution of Halogenated Mandelic Acids through Enantiospecific Co-Crystallization with Levetiracetam.

The resolution of halogenated mandelic acids using levetiracetam (LEV) as a resolving agent via forming enantiospecific co-crystal was presented. Five halogenated mandelic acids, 2-chloromandelic acid (2-ClMA), 3-chloromandelic acid (3-ClMA), 4-chloromandelic acid (4-ClMA), 4-bromomandelic acid (4-BrMA), and 4-fluoromandelic acid (4-FMA), were selected as racemic compounds. The effects of the equilibrium time, molar ratio of the resolving agent to racemate, amount of solvent, and crystallization temperature on resolution performance were investigated. Under the optimal conditions, the resolution efficiency reached up to 94% and the enantiomeric excess (%e.e.) of (R)-3-chloromandelic acid was 63%e.e. All five halogenated mandelic acids of interest in this study can be successfully separated by LEV via forming enantiospecific co-crystal, but the resolution performance is significantly different. The results showed that LEV selectively co-crystallized with S enantiomers of 2-ClMA, 3-ClMA, 4-ClMA, and 4-BrMA, while it co-crystallized with R enantiomers of 4-FMA. This indicates that the position and type of substituents of racemic compounds not only affect the co-crystal configuration, but also greatly affect the efficiency of co-crystal resolution.

Antimicrobial Properties of Mandelic Acid, Gallic Acid and their Derivatives.

PURPOSE: Alpha-hydroxy acids (AHAs) are one of the classes of hydroxy acids being beneficial for human health. The manuscript summarizes the biological properties of two popular members of AHAs, i.e., Mandelic Acid (MA) and Gallic Acid (GA), with particular emphasis on antimicrobial properties. Moreover, attempts to design new derivatives improving the natural properties of AHAs by using the chemical and physical approach are discussed. METHODS: Antimicrobial properties of MA, an arylalkyl AHA containing phenyl group attached to α- carbon, and GA, an aromatic trihydroxybenzoic acid containing the phenolic ring and carboxylic acid functional group, and their derivatives against common human and plant pathogenic fungi have been reviewed. RESULTS: The antimicrobial activity of MA and GA is a complex phenomenon strictly correlated with other properties exhibited by these acids, e.g., pro-oxidative activity and hydrophobicity. In most cases, the acids derivatives exhibited higher antimicrobial activity than the acids themselves. This is probably because of the higher lipophilicity of moiety that allows better penetration through the cell membrane. CONCLUSION: MA and GA present an excellent health-promoting tool and are valuable starting materials for the design of new compounds such as metal complexes with alkali, or alkali earth metals. The lipophilic, antimicrobial, and pro-oxidative properties act synergistically, supporting the pharmacological and therapeutic effect of acids and their derivatives.

Synthesis of (R)-mandelic acid and (R)-mandelic acid amide by recombinant E. coli strains expressing a (R)-specific oxynitrilase and an arylacetonitrilase.

OBJECTIVES: Chiral 2-hydroxycarboxylic acids and 2-hydroxycarboxamides are valuable synthons for the chemical industry. RESULTS: The biocatalytic syntheses of (R)-mandelic acid and (R)-mandelic acid amide by recombinant Escherichia coli clones were studied. Strains were constructed which simultaneously expressed a (R)-specific oxynitrilase (hydroxynitrile lyase) from the plant Arabidopsis thaliana together with the arylacetonitrilase from the bacterium Pseudomonas fluorescens EBC191. In addition, recombinant strains were constructed which expressed a previously described acid tolerant variant of the oxynitrilase and an amide forming variant of the nitrilase. The whole cell catalysts which simultaneously expressed the (R)-specific oxynitrilase and the wild-type nitrilase transformed in slightly acidic buffer systems benzaldehyde plus cyanide preferentially to (R)-mandelic acid with ee-values > 95%. The combination of the (R)-specific oxynitrilase with the amide forming nitrilase variant gave whole cell catalysts which converted at pH-values ≤ pH 5 benzaldehyde plus cyanide with a high degree of enantioselectivity (ee > 90%) to (R)-mandelic acid amide. The acid and the amide forming catalysts also converted chlorinated benzaldehydes with cyanide to chlorinated mandelic acid or chlorinated mandelic acid amides. CONCLUSIONS: Efficient systems for the biocatalytic production of (R)-2-hydroxycarboxylic acids and (R)-2-hydroxycarboxamides were generated.

A Population Pharmacokinetic Model of (R)- and (S-) Oxybutynin and Its Active Metabolites After Oral and Intravesical Administration to Healthy Volunteers.

Oxybutynin is a racemic anticholinergic drug used for the symptomatic treatment of detrusor overactivity. The formation of active metabolites related to tolerability problems depends on the route of administration. The objective of this evaluation was to develop a pharmacokinetic model for oral/intravesical administration as the basis for simulations with different dosages. Data from a published changeover clinical study with 18 healthy adults receiving a single oral dose of 5 mg immediate-release oxybutynin and single and multiple intravesical doses of 10 mg oxybutynin solution was evaluated. Enantioselective plasma concentrations of oxybutynin and N-desethyloxybutynin (NDO) were used to establish a population pharmacokinetic model using nonlinear mixed-effects modeling with NONMEM 7.4.1. For both enantiomers, the data were described well by a 2-compartment model for oxybutynin with an additional compartment for NDO. Oxybutynin absorption was modeled by transit compartments for oral and first-order absorption for intravesical application. Bioavailability of the more active (R)-enantiomer was 7% for oral and 10%-22% for intravesical administration. In simulations, intravesical doses of 5 to 15 mg (R)-oxybutynin administered 2 to 3 times daily decreased peak-trough fluctuations of NDO to 8% compared with 24% after oral administration. The NDO/oxybutynin ratio was reduced from 17 after oral administration to unity. Chronic intravesical versus oral administration of (R)-oxybutynin generates distinctly lower and less variable concentrations of (R)-NDO. Pharmacokinetic simulations suggest that exposure for 12.5 mg (R)-oxybutynin administered twice daily might not compromise efficacy and tolerability compared with exposure for standard thrice-daily administrations. This assumption needs to be assessed in clinical studies.

PEG-modified lipase immobilized onto NH2-MIL-53 MOF for efficient resolution of 4-fluoromandelic acid enantiomers.

A new heterogeneous bio-catalyst was prepared by the immobilization of lipase from Pseudomonas fluorescents (PFL) onto metal-organic frameworks (MOF), NH2-MIL-53(Fe), using covalent cross-linking. The immobilized lipase [PEG-PFL@NH2-MIL-53(Fe)] was firstly applied in enantioselective resolution of 4-fluoromandelic acid (4-FMA) enantiomers. After optimization of the immobilization PFL onto NH2-MIL-53, its loading capacity is 224.5 mg PFL/g MOF. The optimal enzymatic conditions are temperature of 50 °C, VA/4-FMA substrate ratio of 6:1, immobilized lipase loading of 60 mg and reaction time of 12 h. Experimental results show that the catalytic activity and thermal stability of PFL are significantly improved by polyethylene glycol (PEG) modification and immobilization. At 65 °C, the catalytic activity of immobilized lipase retains 86.0% of initial activity. Under the optimal conditions, the excellent results were obtained with conversion of 49.6% and enantiomer excess of 98.0% for the immobilized PFL catalyzed transesterification reaction. Furthermore, the immobilized lipase exhibits excellent cycle stability with 83% of its initial activity after four cycle.

A subtraction fitting method for independent determination of enantioselective and nonselective adsorption isotherms based on the single-component isotherms in the framework of the two-site model.

Based on theory of two-site model, a subtraction fitting method (SFM) is proposed to independently fit enantioselective adsorption sites and the nonselective adsorption sites on the surface of chiral stationary phases (CSP) based on polysaccharide derivatives. Compared with the direct fitting method, the method allows independent fitting the isotherm models of two types of adsorption sites. By the SFM, the adsorption data of methyl mandelate on the CSP based on cellulose tri-(3, 5-dimethylphenylcarbamate) was measured. The adsorption on enantioselective sites was well fitted with Langmuir model, and the adsorption on nonselective sites was well fitted with Tóth model or Langmuir-Freundlich model. The adsorption isotherms of the enantiomers of Corey PG-lactone diol on chiral stationary phase coated with different amounts of amylose tri-(3,5-dimethylphenylcarbamate) (Wchiral selector: Wsilica = 20 : 100, 30: 100 and 40: 100, respectively) were also studied. It was found that the saturated adsorption capacities of both sites increase with the increase of the chiral selector loading. The chiral stationary phase with low chiral selector loading (Wchiral selector: Wsilica = 20 : 100) has a high true separation factor (αtrue = 16.8) and the lowest apparent separation (αapp = 1.70) due to the large nonselective adsorption, which indicates that a chromatographic support with an inert surface is important for this type of CSP.

Enantioseparation of mandelic acid on vancomycin column: Experimental and docking study.

So far, no detailed view has been expressed regarding the interactions between vancomycin and racemic compounds including mandelic acid. In the current study, a chiral stationary phase was prepared by using 3-aminopropyltriethoxysilane and succinic anhydride to graft carboxylated silica microspheres and subsequently by activating the carboxylic acid group for vancomycin immobilization. Characterization by elemental analysis, Fourier transform infrared spectroscopy, solid-state nuclear magnetic resonance, and thermogravimetric analysis demonstrated effective functionalization of the silica surface. R and S enantiomers of mandelic acid were separated by the synthetic vancomycin column. Finally, the interaction between vancomycin and R/S mandelic acid enantiomers was simulated by Auto-dock Vina. The binding energies of interactions between R and S enantiomers and vancomycin chiral stationary phase were different. In the most probable interaction, the difference in mandelic acid binding energy was approximately 0.2 kcal/mol. In addition, circular dichroism spectra of vancomycin interacting with R and S enantiomers showed different patterns. Therefore, R and S mandelic acid enantiomers may occupy various binding pockets and interact with different vancomycin functions. These observations emphasized the different retention of R and S mandelic acid enantiomers in vancomycin chiral column.

Stereoselective Pharmacokinetics and Chiral Inversions of Some Chiral Hydroxy Group Drugs.

BACKGROUND: Chiral safety, especially chiral drug inversion in vivo, is the top priority of current scientific research. Medicine researchers and pharmacists often ignore that one enantiomer will be converted or partially converted to another enantiomer when it is ingested in vivo. So that, in the context that more than 50% of the listed drugs are chiral drugs, it is necessary and important to pay attention to the inversion of chiral drugs. METHODS: The metabolic and stereoselective pharmacokinetic characteristics of seven chiral drugs with one chiral center in the hydroxy group were reviewed in vivo and in vitro including the possible chiral inversion of each drug enantiomer. These seven drugs include (S)-Mandelic acid, RS-8359, Tramadol, Venlafaxine, Carvedilol, Fluoxetine and Metoprolol. RESULTS: The differences in stereoselective pharmacokinetics could be found for all the seven chiral drugs, since R and S isomers often exhibit different PK and PD properties. However, not every drug has shown the properties of one direction or two direction chiral inversion. For chiral hydroxyl group drugs, the redox enzyme system may be one of the key factors for chiral inversion in vivo. CONCLUSION: In vitro and in vivo chiral inversion is a very complex problem and may occur during every process of ADME. Nowadays, research on chiral metabolism in the liver has the most attention, while neglecting the chiral transformation of other processes. Our review may provide the basis for the drug R&D and the safety of drugs in clinical therapy.

Visual chiral recognition of aromatic amino acids with (S)-mandelic acid-based ionic liquids via complexation.

Recently, chiral ionic liquids have attracted increasing attention in analytical chemistry. However, only a few papers focus on the application of them in visual chiral recognition. Herein, two functionalized chiral ionic liquids derived from (S)-mandelic acid (1-butyl-3-methylimidazolium mandelate, CIL1 and N-butyl-N-methylpyrrolidinium mandelate, CIL2) were prepared for visual chiral recognition of aromatic amino acids for the first time. In the presence of Cu(II) and appropriate solvents, visual enantiomeric responses of phenylalanine, tryptophane, tyrosine and phenylglycine were observed. Relying on solubility or color differences, all chiral recognition could be finished within 5 min. The potential mechanism was investigated by means of infrared spectroscopy, ultraviolet spectroscopy, thermal gravity analysis, elemental analysis and scanning electron microscope. Results revealed that CuSO4 interacted with CIL1 and D-tryptophane in the ratio of 1:1.96:0.43 in relevant precipitate, and the different stability of complex was responsible for the chiral recognition. In addition, resolution of racemic tryptophane was performed, which offered excellent enantiomeric excess values (94.2% for CIL1 and 95.1% for CIL2 in solid phase). The proposed ionic liquids had strong enantioselectivity for aromatic amino acids and great potential in visual chiral recognition.

dl-Mandelic acid exhibits high sperm-immobilizing activity and low vaginal irritation: A potential non-surfactant spermicide for contraception.

dl-Mandelic acid (MA), an alpha-hydroxycarboxylic acid, has been widely used as an intermediate of pharmaceutical and fine chemicals. Here, we evaluated the sperm-immobilizing activity of MA and its safety profiles. Spermatozoon motility was assessed by computer-aided sperm analysis, the integrity of the plasma membrane and. mitochondrial potential was assessed using fluorescein isothiocyanate-pisum sativum agglutinin and JC-1, respectively. The local tolerance of the MA-containing gel formulation was evaluated using a rabbit vaginal irritation test. We found that MA inhibited sperm motility and movement patterns in a concentration-dependent manner. Within 20 s, MA-induced spermatozoa immobilization occurred with a minimum effective concentration and a median effective concentration of 0.86 and 0.54 mg/mL, respectively. Plasma membrane disruptions of MA-treated spermatozoa were relatively mild, but mitochondrial depolarization occurred. Histopathological examination showed that MA exposure did not exert obvious effects on the integrity of spermatozoa membrane structures and only caused slight irritation to the rabbit vaginal epithelium. The vaginal irritation scores of the vehicle control and the nonoxynol -9 gel control groups were 1.38 ± 0.65 and 7.88 ± 1.67, respectively (p < 0.01), whereas those of the MA gel groups at 10, 20, and 40 mg/mL were 1.69 ± 1.04, 2.98 ± 0.77, and 4.35 ± 1.04 with p values of >0.05, >0.05, and <0.05 (vs. vehicle control), respectively, which were within the clinically acceptable range (<8). Therefore, our results confirmed that MA exhibited significant sperm-immobilizing effects and caused mild plasma membrane injury, suggesting that it has potential for development as a future non-surfactant spermicide.

In the Mists of a Fungal Metabolite: An Unexpected Reaction of 2,4,5-Trimethoxyphenylglyoxylic Acid.

The reactions of phenylglyoxylic acids during the synthesis and biological evaluation of fungal metabolites led to the discovery of hitherto unknown compounds with a p-quinone methide (p-QM) structure. The formation of these p-QMs using 13C-labelled starting materials revealed a key-step of this reaction being a retro-Friedel-Crafts alkylation.

Upscale production of (R)-mandelic acid with a stereospecific nitrilase in an aqueous system.

(R)-Mandelic acid (R-MA) is a key precursor for the synthesis of semi-synthetic penicillin, cephalosporin, anti-obesity drugs, antitumor agents, and chiral resolving agents for the resolution of racemic alcohols and amines. In this study, an enzymatic method for the large-scale production of R-MA by a stereospecific nitrilase in an aqueous system was developed. The nitrilase activity of the Escherichia coli BL21(DE3)/pET-Nit whole cells reached 138.6 U/g in a 20,000-L fermentor. Using recombinant E. coli cells as catalyst, 500 mM R,S-mandelonitrile (R,S-MN) was resolved into 426 mM (64.85 g/L) R-MA within 8 h, and the enantiomeric excess (ee) value of R-MA reached 99%. During the purification process, pure R-MA with a recovery rate of 78.8% was obtained after concentration and crystallization. This study paved the foundation for the upscale production of R-MA using E. coli whole cells as biocatalyst.

Preparation and application of teicoplanin functionalized polymeric monolith for enantioseparation of chiral drugs.

A novel chiral stationary phase (CSP), based on a monolithic organic polymer chemically modified with teicoplanin, was fabricated within a 100 µm I.D. fused silica capillary. The teicoplanin was firstly derivatized with 2-isocyanatoethyl methacrylate (ICNEML) and then thermally co-polymerized with the crosslinker ethylene dimethacrylate (EDMA) in presence of porogens (methanol and dimethylsulfoxide). The optimal experimental conditions (e.g., concentration and ratio of the reagents), considering enantioresolution and permeability, were systematically investigated. The prepared monolith was evaluated using scanning electron microscopy, and the column exhibited quite good morphology. In order to further evaluate the enantioresolving power of the poly(ICNEML-teicoplanin-co-EDMA) monolith, a series of basic and acidic chiral compounds were analyzed using an isocratic mode of polar organic solvents (methanol and acetonitrile) or the same solvents in combination with water (reversed-phase) by nano-liquid chromatography. Five mandelic acids and six derivatized amino acids were enantioresolved under reversed-phase mode (Rs = 1.22-3.47 and α = 1.43-6.33). This monolithic teicoplanin-CSP was also effective in the enantioseparations of 17 amino alcohol drugs employing polar-organic phase mode (MeOH/ACN/TEA/HOAc (80/20/0.03/0.055, v/v/v/v)). Ten of them were baseline enantioresolved (alprenolol, betaxolol, clenbuterol, isoproterenol, metoprolol, pindolol, propranolol, salbutamol, sotalol, tertatolol) (Rs = 1.55-2.48 and α = 1.21-1.55), while the others were partially enantioseparated (Rs = 1.14-1.48).

Diversity of complexes based on p-nitrobenzoylhydrazide, benzoylformic acid and diorganotin halides or oxides self-assemble: Cytotoxicity, the induction of apoptosis in cancer cells and DNA-binding properties.

Eight organotin(IV) complexes (C1-C8) have been synthesized and characterized by elemental analysis, fourier transform infrared spectroscopy (FT-IR), multinuclear nuclear magnetic resonance (1H, 13C and 119Sn NMR), high resolution mass spectroscopy (HRMS) and single crystal X-ray structural analysis. Crystallographic data show that C1 was a tetranuclear 16-membered macrocycle complex, C2-C4 and C7 were centrosymmetric dimer distannoxane and there was a Sn2O2 four-membered ring in the middle of the molecule, respectively, C5 and C6 are monoorganotin complexes due to the dehydroalkylation effect during the reaction, while C8 forms a one-dimensional chain structure. The cytotoxicity of all complexes were tested by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assays against three human tumor cell lines NCI-H460, MCF-7 and HepG2. The dibutyltin complex C2 has been shown to be more potent antitumor agents than other complexes and carboplatin. Cell apoptosis study of C2 with the high activity on HepG2 and MCF-7 cancer cell lines was investigated by flow cytometry, it was shown that the antitumor activity of C2 was related to apoptosis, but it has different cell cycle arrest characteristics from platinum compounds, and the proliferation was inhibited by blocking cells in S phase. The DNA binding activity of the C2 was studied by UV-visible absorption spectrometry, fluorescence competitive, viscosity measurements and gel electrophoresis, results shown C2 can be well embedded in the double helix of DNA and cleave DNA.

Anti-leishmanial activity and cytotoxicity of a series of tris-aryl Sb(V) mandelate cyclometallate complexes.

A series of ten cyclometallates and two µ2-peroxo bridged tris-aryl Sb(V) complexes derived from R/S-mandelic acid (= R/S-ManH2) were synthesised and characterised. As confirmed by X-ray crystallography the complexes 1Sr/s, [Sb(o-tol)3(man)], 2Sr/s, [Sb(m-tol)3(man)], 4Sr/s, [Sb(o-PhOMe)3(man)], 5Sr/s, [Sb(Mes)3(man)] and 6Sr/s, [Sb(p-tert-BuPh)3(man)] are all cyclometallates. Complexes 3Sr/s, [(Sb(p-tol)3(manH)2O2], contain a bridging O22- anion in the solid-state but convert to the cyclometallates in DMSO solution with concomitant release of H2O2 and formation of complexes [Sb(p-tol)3(man)], 3Sr'/s'. All complexes underwent initial testing against both human fibroblasts and L. major V121 promastigotes. IC50 values were found to range from 2.07 (6Sr) to >100 (4Sr) µM and 0.21 (5Ss) to >100 (4Ss) µM for fibroblasts and parasites respectively. Two of the complexes were found to be ineffective, displaying no toxicity (4S/r). Despite the degree of mammalian toxicity, the selectivity of most complexes exceeded an SI of three and so were assessed for their anti-amastigote activity. Excellent anti-amastigote activity was observed for complexes at both 10 µM and 5 µM, with percentage infection value ranging from 0.15-3.00% for those tested at 10 µM and 0.25-2.50% for those at 5 µM.

Development of a dispersive liquid-liquid microextraction method based on a ternary deep eutectic solvent as chelating agent and extraction solvent for preconcentration of heavy metals from milk samples.

A simple, green, rapid, and efficient ligandless dispersive liquid-liquid microextraction procedure based on solidification of a ternary deep eutectic solvent has been proposed for the extraction of trace amounts of Cd(II), Cu(II), and Pb(II) ions in milk samples prior to their determination by flame atomic absorption spectrometry. Initially, a suitable mole ratio of sorbitol, menthol, and mandelic acid are mixed in a test tube, and after heating, a deep eutectic solvent with low density compared to water is formed. The synthesized solvent is used as a chelating agent and an extraction solvent in the extraction of some heavy metal ions from milk samples. The influence of several effective parameters on the responses and extraction recoveries of the analytes was investigated. Under the optimum experimental conditions, the linear ranges were in the ranges of 1.0-40 µg L-1 for Cd(II) and Pb(II), and 1.0-25 µg L-1 for Cu(II). The obtained relative standard deviations (n = 6, C = 2.5 µg L-1 of each cation) and detection limits were in the ranges of 3.4-4.1% and 0.38-0.42 µg L-1, respectively. Finally, the developed method was successfully applied for the determination of Cd(II), Cu(II), and Pb(II) ions in different milk samples.