Technical features of vaping drug delivery system for bronchodilator delivery.

PURPOSE: Several technical features influencing bronchodilator delivery were evaluated using different vaping drug delivery systems (VDDS). METHODS: Terbutaline in powder form, combined with 1, 3- propanediol used as e-liquid was tested at different concentrations (1 and 2.5 mg/mL), power levels (15 W and 30 W), and set applied resistances (0.15 to 1.5 O) to compare the efficiency of three VDDS (GS AIR2, GS TANK, CUBIS). Samples were collected with a Glass Twin Impinger (GTI). A High Performance Liquid Chromatography (HPLC) was used for drug quantification. The Next Generation Impactor (NGI) measured particle size distribution. Results were also considered with a clinical jet nebulizer (Cirrus TM 2, 2 mL of terbutaline at 2.5 mg/mL). RESULTS: GS AIR2 with resistance = 1.5 O; power = 15 W, and [Terbutaline] = 2.5 mg/mL represents the optimal VDDS conditions to deliver a respirable dose of 20.05 ± 4.2 µg/puff with a mass median aerodynamic diameter (MMAD) of 1.41 ± 0.03 µm. Thus, 52 puffs were required (lasting approximately 15 min of vaping) to reach similar respirable dose and MMAD compared to nebulization. CONCLUSION: We proved that several crucial VDDS technical parameters govern the performance of respiratory bronchodilator delivery including the resistance, power level and atomizer design.

Early potential evaluation of lead compounds from a DNA-encoded library by the determination of their thermodynamics through a chromatographic method based on immobilized ß2-adrenoceptor.

Early potential evaluation of lead compounds is critical to decrease downstream lead-optimization cycle times and clinical attrition rates for drug development. This increasingly necessitates the methodologies for accurately evaluating the potential compounds. This work immobilized ß2-adrenoceptor (ß2-AR) onto microspheres through Halo-tag mediated reaction. Characterizing the resulting microspheres by elemental and functional analysis, we utilized the immobilized receptor to determine the thermodynamics of terbutaline, tulobuterol, clorprenaline, salbutamol, and methoxyphenamine. The association constants correlated to their capacity factors on the column containing the immobilized ß2-AR, thus providing a possibility for early potential evaluation of lead compounds from complex matrices like a DNA-encoded library. By this model, the lead compound (XC267) was predicted to have an association constant higher than terbutaline, salbutamol, and methoxyphenamine, but lower than tulobuterol and clorprenaline. The binding interaction between XC267 and ß2-AR is a spontaneous endothermic process with an association constant of (6.62 ± 0.13) × 104 M-1 at 37 °C. The change of Gibbs free energy(ΔGθ), enthalpy change (ΔHθ), and entropy change (ΔSθ) was -28.49 kJ/mol, -10.58 kJ/mol, and 57.79 J/moL·K at 37 °C. By the semi-empirical rule of Ross, the driving force of the interaction between XC267 and ß2-AR was electrostatic interaction. Such binding force was also achieved by molecular docking. These results suggested that XC267 is a candidate to treat asthma by specific binding to ß2-AR. We reasoned that receptor chromatography is able to the early potential evaluation of lead compounds from complex matrices.

[Detection and Analysis of Drug Crystals in Medical Transdermal Patches by Using X-ray Diffraction Measurement].

The crystallization of active pharmaceutical ingredients (APIs) in matrix-type transdermal patches has implications for the rate of drug absorption through the skin and patch adhesion strength. Therefore, the presence or absence and the degree of API crystallinity must be controlled to guarantee the quality of patches. In this study, the utility of laboratory-level X-ray diffractometers for the detection and analysis of crystalline APIs in transdermal patches was investigated using medical patches of tulobuterol and isosorbide dinitrate. Several matrix-type patches employ a controlled drug delivery system containing intentionally crystallized API. Both benchtop and high-resolution laboratory X-ray diffractometers can detect several characteristic peaks of the APIs in these patches even if the patches are wrapped in an outer bag, although a benchtop model provides peak heights one-seventh to one-fifth that of a high-resolution instrument. An isosorbide dinitrate patch containing an unintentionally crystallized spot was wrapped in an outer bag, followed by measurements using both X-ray diffractometers. For both instruments, several isosorbide dinitrate-derived peaks were detected only at the crystallized spot, although the signal-to-noise ratio was poorer for the benchtop model. These results show that a high-resolution X-ray diffractometer is advantageous for high-detection sensitivity and offers a high degree of freedom of the measurement position on the sample. It was concluded that a laboratory-level high-resolution X-ray diffractometer can be used to examine the crystalline state of APIs in patches inside an unopened outer bag.

The interaction of a ß2 adrenoceptor agonist drug with biomimetic cell membrane models: The case of terbutaline sulphate.

Terbutaline sulphate (TS) is a selective short-acting ß2 adrenoceptor agonist used for asthma treatment. The pharmacological activity of TS depends on its binding to the transmembrane protein, ß2 adrenoceptor. Thus, the interactions of this drug with biological membranes are expected, affecting its pharmacological activity. Using in vitro models to study the interaction of TS with biological membranes can provide important information about the activity of the drug. Here, liposomes with different lipid compositions were used as biomimetic models of cell membranes to evaluate the effect of composition, complexity, and physical state of membranes on TS-membrane interactions. For that, liposomes containing dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and liposomes containing DMPC and cholesterol (CHOL) were prepared. For the study of TS-membrane interactions, the TS lipophilicity was evaluated in terms of i) partition coefficient; ii) the preferential location of the drug within the membrane; iii) and the effect of TS on the membrane fluidity. The obtained data suggest that TS has an affinity for the lipid membrane, partitioning from the aqueous to the lipid phase. The affinity was dependent on the liposomes' compositions, showing a greater affinity for DMPC membranes than for DMPC:CHOL model. Dynamic light scattering (DLS) results revealed that this is due to the rigidizing effect caused by CHOL molecules. These findings provide valuable insights in the understanding of the complex interaction of TS with biomembrane models as well as the relevance of lipid compositions and membrane structure in such interactions, which may be related to its pharmacological activity and side effects.

Identification of Compounds for Butyrylcholinesterase Inhibition.

Butyrylcholinesterase (BChE) is a nonspecific cholinesterase enzyme that hydrolyzes choline-based esters. BChE plays a critical role in maintaining normal cholinergic function like acetylcholinesterase (AChE) through hydrolyzing acetylcholine (ACh). Selective BChE inhibition has been regarded as a viable therapeutic approach in Alzheimer's disease. As of now, a limited number of selective BChE inhibitors are available. To identify BChE inhibitors rapidly and efficiently, we have screened 8998 compounds from several annotated libraries against an enzyme-based BChE inhibition assay in a quantitative high-throughput screening (qHTS) format. From the primary screening, we identified a group of 125 compounds that were further confirmed to inhibit BChE activity, including previously reported BChE inhibitors (e.g., bambuterol and rivastigmine) and potential novel BChE inhibitors (e.g., pancuronium bromide and NNC 756), representing diverse structural classes. These BChE inhibitors were also tested for their selectivity by comparing their IC50 values in BChE and AChE inhibition assays. The binding modes of these compounds were further studied using molecular docking analyses to identify the differences between the interactions of these BChE inhibitors within the active sites of AChE and BChE. Our qHTS approach allowed us to establish a robust and reliable process to screen large compound collections for potential BChE inhibitors.

Novel lipid-polymer hybrid nanoparticles incorporated in thermosensitive in situ gel for intranasal delivery of terbutaline sulphate.

AIM: The present work aimed to improve the bioavailability of terbutaline sulphate (TS) and to prolong its nasal residence time for the treatment of asthma. METHODS: Chitosan/pectin polyelectrolyte complex nanoparticles (CS/PC) were prepared by ionic gelation method and coated with phospholipid (PL) and then incorporated into optimised thermosensitive in situ gel. RESULTS: The optimal PL-coated nanoparticle formulation (LP1) showed the smallest particle size (345.5 nm), the highest zeta potential (32.9 mV) and the greatest percent drug released after 6 h (71%). The optimum in situ gel loaded with LP1 (NG3) showed three times greater permeation through nasal mucosa than aqueous solution of TS and revealed about 94% and 92% of the effect of IV injection of drug solution on tidal volume and peak expiratory flow in histamine treated rats, respectively. CONCLUSION: The developed PL-coated CS/PC/in situ gel could be considered as a promising intranasal formulation of TS for asthma management.

Cold Flow Evaluation in Transdermal Drug Delivery Systems by Measuring the Width of the Oozed Adhesive.

The objective of this study was to develop a simpler and more practical quantitative evaluation method of cold flow (CF) in transdermal drug delivery systems (TDDSs). CF was forcibly induced by loading a weight on a punched-out sample (bisoprolol and tulobuterol tapes). When the extent of CF was analyzed using the area of oozed adhesive as following a previously reported method, the CF profiles were looked different between the samples 12 mm in diameter subjected to a 0.5-kg weight and samples 24 mm in diameter subjected to a 2.0-kg weight despite an equal load per unit area (4.42 g/mm2). The width of oozed adhesive around the original sample was suggested to be an index that properly describes the relationship between the load per unit area and the extent of CF. Further, it was clarified that the average CF width over the entire circumference of the sample was the same whether the samples were round or square as long as the sample area and load were the same. We also observed a linear relationship between the CF width and the aspect ratio of oval and rectangular samples. These results indicated that the CF properties of typical TDDS products lacking CF-proof processing at the edges could be determined by testing samples cut from the product rather than the whole TDDS patch. The proposed width measuring method was simple and useful for optimizing the composition of the adhesive and for testing the quality of the product.

Separation of terbutaline enantiomers in capillary electrophoresis with neutral cyclodextrin-type chiral selectors and investigation of the structure of selector-selectand complexes using nuclear magnetic resonance spectroscopy.

The major goal of this study was to determine the affinity pattern of the terbutaline (TB) enantiomers toward α-, ß-, γ-, and heptakis(2,3-di-O-acetyl)-ß-cyclodextrins and using NMR spectroscopy for the understanding of the fine mechanisms of interaction between the cyclodextrins (CD) and TB enantiomers. It was shown once again that CE in combination with NMR spectroscopy represents a sensitive tool to study the affinity patterns and structure of CD complexes with chiral guests. Opposite affinity patterns of TB enantiomers toward native α- and ß-CDs were associated with significant differences between the structure of the related complexes in solution. In particular, the complex between TB enantiomers and α-CD was of the external type, whereas an inclusion complex was formed between TB enantiomers and ß-CD. One of the possible structures of the complex between TB and heptakis(2,3-di-O-acetyl)-ß-CD (HDA-ß-CD) was quite similar to that of TB and ß-CD, although the chiral recognition pattern and enantioselectivity of TB complexation with these two CDs were very different.

Preparation of a thiols ß-cyclodextrin/gold nanoparticles-coated open tubular column for capillary electrochromatography enantioseparations.

Inspired by the distinct chemical and physical properties of nanoparticles, here a novel open-tubular capillary electrochromatography column was prepared by electrostatic assembly of poly(diallydimethylammonium chloride) onto the inner surface of a fused-silica capillary, followed by self-adsorption of negatively charged SH-ß-cyclodextrin/gold nanoparticles. The formation of the SH-ß-cyclodextrin/gold nanoparticles coated capillary was confirmed and characterized by scanning electron microscopy and energy dispersive spectrometry. The results of scanning electron microscopy and energy dispersive spectrometry studies indicated that SH-ß-cyclodextrin/gold nanoparticles were successfully coated on the inner wall of the capillary column. The performance of the SH-ß-cyclodextrin/gold nanoparticles coated capillary was validated by the analysis of six pairs of chiral drugs, namely zopiclone, carvedilol, salbutamol, terbutaline sulfate, phenoxybenzamine hydrochloride, and ibuprofen. Satisfactory enantioseparation results were achieved, confirming the use of gold nanoparticles as the support could enhance the phase ratio of the open-tubular capillary column. Additionally, the stability and reproducibility of the SH-ß-cyclodextrin/gold nanoparticles coated capillary column were also investigated. Then, this proposed method was well validated with good linearity (≥0.999), recovery (90.0-93.5%) and repeatability, and was successfully used for enantioseparation of ibuprofen in spiked plasma samples, which indicated the new column's potential usage in biological analysis.

A novel nanogel loaded with chitosan decorated bilosomes for transdermal delivery of terbutaline sulfate: artificial neural network optimization, in vitro characterization and in vivo evaluation.

The objective of the present work was to formulate, optimize, and evaluate transdermal terbutaline sulfate (TBN)-loaded bilosomes (BLS) in gel, compared to conventional oral TBN solution and transdermal gel loaded with free TBN, aiming at evading the hepatic first-pass metabolism. A face-centered central composite design was adopted to observe the effects of different formulation variables on TBN-BLS, and artificial neural network (ANN) modeling was employed to optimize TBN-BLS. TBN-BLS were prepared by a thin film hydration method integrating soybean phosphatidylcholine and cholesterol as a lipid phase and sodium deoxycholate (SDC) as a surfactant with or without the coating of chitosan (CTS). After being subjected to physicochemical characterization, TBN-BLS were enrolled in a histopathological study and pharmacokinetic investigation in a rat model. The optimized TBN chitosan-coated bilosomes (TBN-CTS-BLS) were spherical vesicles (245.13 ± 10.23 nm) with adequate entrapment efficiency (65.25 ± 5.51%) and good permeation characteristics (340.11 ± 22.34 µg/cm2). The TBN-CTS-BLS gel formulation was well-tolerated with no inflammatory signs manifested upon histopathological evaluation. The pharmacokinetic study revealed that the optimized TBN-CTS-BLS formulation successively enhanced the bioavailability of TBN by about 2.33-fold and increased t1/2 to about 6.21 ± 0.24 h as compared to the oral solution. These findings support the prospect use of BLS as active and safe transdermal carrier for TBN in the treatment of asthma. Graphical Abstract.

Comparative analysis of the full set of methylated ß-cyclodextrins as chiral selectors in capillary electrophoresis.

The chiral separation ability of the full library of methylated-ß-cyclodextrins towards pharmacologically significant racemic drugs including basic compounds was studied by chiral CE. The syntheses of all the methylated, single isomer ß-cyclodextrins were revised and optimized and the aqueous solubility of the derivatives was unambiguously established. The three most relevant commercially available methylated isomeric mixtures were also included in the screening, so a total of ten various methylated CDs were investigated. The effects of the selector concentration on the enantiorecognition properties at acidic pH were investigated. Among the dimethylated ß-cyclodextrins, the heptakis (2,6-di-O-methyl)-ß-cyclodextrin isomer (2,6-DIMEB) resulted to be the most versatile chiral selector. Terbutaline was selected as a model compound for the in-depth investigation of host-guest enantiodiscrimination ability. The association constants between the two terbutaline enantiomers and 2,6-DIMEB were determined in order to support that the enantioseparation is driven by differences is host-guest binding. The migration order of the enantiomers was confirmed by performing spiking experiments with the pure enantiomers. 1D and 2D NMR spectroscopy was applied to the 2,3-, and 2,6-DIMEB/terbutaline systems to rationalize at molecular level the different enantioseparation ability of the dimethylated ß-cyclodextrin selectors.

In situ immobilization of sulfated-ß-cyclodextrin as stationary phase for capillary electrochromatography enantioseparation.

In this work, a novel sulfated-ß-cyclodextrin (S-ß-CD) coated stationary phase was prepared for open-tubular capillary electrochromatography (OT-CEC). The capillary was developed by attaching polydopamine/sulfated-ß-cyclodextrin (PDA/S-ß-CD) onto the gold nanoparticles (AuNPs) coated capillary which was pretreated with polydopamine. The results of scanning electron microscopy (SEM) and energy dispersive X-ray analysis spectroscopy (EDS) indicated that polydopamine/sulfated-ß-cyclodextrin was successfully fixed on the gold nanoparticles coated capillary. To evaluate the performance of the prepared open tubular (OT) column, the enantioseparation was carried out by using ten chiral drugs as model analytes. Under the optimal conditions, salbutamol, terbutaline, trantinterol, tulobuterol, clorprenaline, pheniramine, chlorpheniramine, brompheniramine, isoprenaline and tolterodine were baseline separated with the resolution (Rs) values of 3.25, 1.76, 2.51, 1.89, 3.17, 2.17, 1.99, 1.72, 2.01 and 3.20, respectively. Repeatability of the column was studied, with the relative standard deviations for run-to-run, day-to-day and column-to-column lower than 5.7%.

Contrasting photoreactivity of ß2-adrenoceptor agonists Salbutamol and Terbutaline in the presence of humic substances.

The photodegradation reactions of two typical ß2-adrenoceptor agonists, salbutamol (SAL) and terbutaline (TBL), alone, and in the presence of Aldrich humic acid (AHA) or Suwannee River fulvic acid (SRFA) were investigated by steady-state photolysis experiments, laser flash photolysis (LFP), kinetic modeling and quantum calculation. AHA and SRFA (2-20 mgC L-1) accelerated the phototransformation of both SAL and TBL. For SAL, an inhibiting effect of oxygen on the photodegradation was observed that is fully consistent with the main involvement of excited triplet states of HS (3HS*). On the contrary, oxygen drastically enhanced the photodegradation of TBL showing that 3HS* were negligibly involved in the reaction. The involvement of singlet oxygen was also ruled out because of the low reaction rate constant measured between TBL and singlet oxygen. Quantum calculations were therefore performed to explore whether oxygenated radicals could through addition reactions explain the differences of reactivity of TBL and SAL in oxygen medium. Interestingly, calculations showed that in the presence of oxygen, the addition of phenoxyl on TBL led to the formation of adducts and to the loss of TBL while the same addition reaction on SAL partly regenerated the starting compound and at the end degraded SAL less efficiently. This study is of high relevance to understand the processes involved in SAL and TBL phototransformation and the photoreactivity of HS. Moreover, our findings suggest that TBL might be a promising probe molecule to delineate the role of oxygenated radicals.

Rapid and mild fabrication of protein membrane coated capillary based on supramolecular assemble for chiral separation in capillary electrochromatography.

Exploration of the simple and stable coating methods is of great significance in capillary electrochromatography (CEC). In this work, a lysozyme assemble supramolecular membrane coated capillary column was developed for CEC chiral separation. Taking advantage of phase transformation of lysozyme, the coating process was achieved within 1.0 h thus to a large extent reduced the capillary preparation time and simplified the coating procedure. The successful fabrication of the supramolecular membrane coated capillary was verified by scanning electron microscopy (SEM), Fourier transform-infrared spectroscopy (FT-IR), fluorescence imaging, and electroosmotic flow (EOF). The separation capacity of the coated capillary was evaluated by analysis of different chiral analytes, including chiral amine drug and neurotransmitters, and good enantioseparation efficiency was achieved for the three pairs of enantiomers. For three consecutive runs, the relative standard deviations (RSD) for the migration time of the analytes for intra-day (n = 3), inter-day (n = 3) and column-to-column (n = 3) were in the range of 0.7-1.5%, 2.7-3.6%, and 4.5-5.8%, respectively. Additionally, the supramolecular membrane coated capillary column could run consecutively 100 times without observable change in the separation efficiency, proving the feasibility of the coating method based on the adhesion of the protein-based supramolecular membrane.

Separation of terbutaline enantiomers in capillary electrophoresis with cyclodextrin-type chiral selectors and investigation of structure of selector-selectand complexes.

The affinity pattern of terbutaline enantiomers towards various cyclodextrins was studied using capillary electrophoresis. The affinity pattern of terbutaline enantiomers was the same towards all studied cyclodextrins except heptakis(2-O-methyl-3,6-di-O-sulfo)-ß-CD. Nuclear magnetic resonance spectroscopy was used for understanding of fine structural mechanisms of interactions of ß-cyclodextrin and its two sulfated derivatives with the enantiomers of terbutaline. The structure of terbutaline complexes with all 3 cyclodextrins studied was different from each other. In confirmation with our earlier studies it was shown again that capillary electrophoresis represents very sensitive technique for studies of affinity patterns in cyclodextrin complexes with chiral guests. Other instrumental (e.g. NMR spectroscopy and X-ray diffraction analysis) and theoretical techniques, although very useful for obtaining the information regarding the stoichiometry, binding constants and structure of intermolecular complexes, as well as about the forces involved in selector-selectand binding and chiral recognition, may sometimes fail to properly sense those fine differences in the affinity patterns. Therefore, it is recommended to use capillary electrophoresis in order to examine correctness of affinity pattern determined for intermolecular complexes of cyclodextrins with guest molecules by other instrumental or computation techniques.

Enantioselective resolution of Rac-terbutaline and evaluation of optically pure R-terbutaline hydrochloride as an efficient anti-asthmatic drug.

Terbutaline is a ß2 -adrenoceptor agonist for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Among the two isomers of terbutaline (TBT 2), R-isomer was found to be the potent enantiomer in generating therapeutic effect, while S-isomer has been reported to show side effects. In this study, R-terbutaline hydrochloride (R-TBH 6) was synthesized through chiral resolution from the racemic terbutaline sulfate (rac-TBS 1) with 99.9% enantiomeric excess (ee) in good overall yield (53.6%). Further, R-TBH 6 nebulized solution was prepared in half dosage of Bricanyl®, which is a marketed product of racemic terbutaline and evaluated in vitro aerosol performance and in vivo anti-asthmatic effect on guinea pigs via. pulmonary delivery. From the investigation, it is evident that R-TBH 6 nebulized solution of half dosage performed similar fine aerosol characteristics and anti-asthmatic effect with Bricanyl®.

Preparation of a Sustained-Release Nebulized Aerosol of R-terbutaline Hydrochloride Liposome and Evaluation of Its Anti-asthmatic Effects via Pulmonary Delivery in Guinea Pigs.

An aerosolized liposome formulation for the pulmonary delivery of an anti-asthmatic medication was developed. Asthma treatment usually requires frequent administration of medication for a sustained bronchodilator response. Liposomes are known for their sustained drug release capability and thus would be a suitable delivery system for prolonging the therapeutic effect of anti-asthmatic medication. Liposomes prepared by thin film hydration were loaded with a model drug, R-terbutaline hydrochloride(R-TBH), using an ammonium sulfate-induced transmembrane electrochemical gradient. This technique provided an encapsulation efficiency of up to 71.35% and yielded R-TBH liposomes with a particle size of approximately 145 ± 20 nm. According to stability studies, these R-TBH liposomes should be stored at 4°C before usage. Compared to R-TBH solution, which showed 90.84% release within 8 h, liposomal R-TBH had a cumulative release of 73.53% at 37°C over 192 h. A next generation impactor (NGI) was used to analyze the particle size distribution in the lungs of R-TBH liposome aerosol in vitro at 5°C. The therapeutic efficacy of the nebulized aerosol of the R-TBH liposomes was assessed via pulmonary delivery in guinea pigs. The results showed that, compared to the R-TBH solution group, the R-TBH liposome group had a prolonged anti-asthma effect.

Effect of Relative Humidity on Bipolar Electrostatic Charge Profiles of dry Powder Aerosols.

PURPOSE: This work investigated the effect of relative humidity (RH) on bipolar electrostatic charge profiles of dry powder inhaler aerosols using the Bipolar Charge Analyzer (BOLAR). METHODS: Two commercial products, Pulmicort® (400 µg, budesonide) and Bricanyl® (500 µg, terbutaline sulfate) Turbuhaler®, were used as model dry powder inhalers (DPIs) in this study. Three individual doses from each Turbuhaler® were sampled at 15, 40, 65 and 90% RH. Subsequently, charge and mass profiles were determined for each dispersion. RESULTS: The aerosols from these two Turbuhaler® DPI were bipolarly charged, with larger particles carrying negative charge and smaller particles positive charge. Particles changed polarity around 2.60-4.17 µm and 0.95-2.60 µm for Pulmicort® and Bricanyl®, respectively. The effect of RH on particles differed between DPIs even though the mass output was not significantly affected. The net charge profiles of Pulmicort® were relatively independent of RH, whereas those of Bricanyl® showed a reduction in the charge magnitude with increasing RH. Both positive and negative charge profiles followed a similar trend with the change in RH and individually they had higher magnitudes than the measured net charge. CONCLUSIONS: This study showed drug-specific bipolar charging of the Turbuhaler® DPI aerosols at varied RHs. Bricanyl® was more susceptible to RH and showed decreased bipolar and net charge levels with increasing RH, in comparison to Pulmicort®.

Green Synthesis of (R)-Terbutaline for Recyclable Catalytic Asymmetric Transfer Hydrogenation in Ionic Liquids.

We synthesize optically active (R)-terbutaline 2, which is an anti-asthmatic drug, through recyclable catalytic asymmetric transfer hydrogenation (RCATH). Various chloroketones 4 were prepared and RCATH was performed on them. The products exhibit moderate to high enantioselectivity. In particular, the hydrogenation of acyl substituted substrates 4c yields chiral secondary alcohols 5c in good yield and enantioselectivity. Furthermore, (R)-terbutaline 2 can be synthesized in one step from the resulting secondary alcohol 5 without racemization.

Design, synthesis and biological evaluation of bambuterol analogues as novel inhibitors of butyrylcholinesterase.

An increase activity of butyrylcholinesterase is believed to contribute to Alzheimer's disease. Bambuterol is a known potent inhibitor of butyrylcholinesterase, but it has undesired cardiac effects and less lipophilicity. Thirteen bambuterol analogues were synthesized using 1-(3, 5-dihydroxyphenyl) ethanone as a starting material. In-vitro cholinesterase assay established that the majority of the compounds are specific butyrylcholinesterase inhibitors. Out of the 13 compounds, two bambuterol derivatives, BD-6 and BD-11 exhibited similar efficacies in inhibiting butyrylcholinesterase with fewer effects on heart and enhanced possibilities of permeating through the blood-brain barrier as compared to bambuterol. These bambuterol analogues may provide better alternatives for treatments of Alzheimer's disease.