Kinetic Solubility Research Articles

Enhanced penetration and anti-psoriatic efficacy of curcumin by improved smartPearls technology with the addition of glycyrrhizic acid

smartPearls technology is one appropriate method to produce anti-psoriatic curcumin (Cur) topical delivery system. To prevent the sedimentation of loaded silica and release changing over the storage, which are disadvantages of smartPearls production, extra glycyrrhizic acid (GA) was added in classical smartPearls ingredients (active and porous material) to get an improved smartPearls production (Cur-GA-silica). The capacity of Cur-GA-silica to remain the gelation state after mixing with water was superior compared to that of the solid cluster without GA and that of the physical mixture of Cur, GA and silica. The Cur-GA-silica practically contained Cur with 1.68% ± 0.12% and showed significant difference with Cur raw drug powder in kinetic solubilities (4.55±0.78µg/mL vs 0 in 5min; 3.26±0.17µg/mL vs 0 in 4h) which was traceable to the amorphous state of Cur-GA-silica detected by X-ray diffractometer. With the amorphous Cur, two times as much penetrated Cur in Cur-GA-silica as in Cur raw drug powder was achieved on the imiquimod-induced psoriasis-like mice model. The anti-psoriatic efficacy of Cur-GA-silica was confirmed by Psoriasis Area and Severity Index (PASI) evaluation, histological evaluation and decreased IL-17A in the imiquimod-induced psoriasiform mouse skin analyzed by enzyme-linked immunosorbent assay. In conclusion, with the addition of GA, a stable amorphous curcumin topical vehicle fabricated by smartPearls technology without extra dermal matrix is available and facilitates penetration efficacy and anti-psoriatic capacity in imiquimod-induced psoriasiform mice.

Synthesis, physico-chemical properties and microsomal stability of compounds bearing aliphatic trifluoromethoxy group

Effects of the trifluoromethoxy substituent on physico-chemical properties of compounds, such as kinetic solubility, lipophilicity and microsomal clearance, was studied in a series of aliphatic derivatives. It was found that kinetic solubility of the CF3O-containing compounds was comparable to that of analogs, i.e. compounds bearing CH3O and CF3 moieties. The CF3O-substituted compounds had higher lipophilicity as compared to methoxy analogues, and nearly the same like CF3-bearing compounds. Microsomal stability studies indicated that the trifluoromethoxy group typically decreased metabolic stability of the corresponding derivatives as compared to either CH3O- or CF3-substituted counterparts, except for N-alkoxy(sulfon)amide series.

Enhanced solubility of microwave-assisted synthesized acyclovir Co-crystals

This study aimed to enhance the kinetic solubility of ACV by using microwave-assisted technique to form ACV co-crystals and overcome its limited aqueous solubility. Co-crystallization is one of the commonly used techniques to improve the dissolution rates of active pharmaceutical ingredients (APIs). Acyclovir (ACV) has a limited efficacy due to its low oral bioavailability resulted from its poor aqueous solubility and permeability. Acyclovir co-crystals were formulated by microwave assisted solvent extraction (MASE) in equimolar ratio of 1:1 with different co-formers. Physical and structural characterization by differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), and Fourier transform infrared (FTIR) spectroscopy were performed. Further evaluation of the co-crystals solubility, dissolution rate and content were carried out using the ultraviolet (UV) spectrophotometry. Co-crystals of acyclovir and tartaric acid (ACV-TA) in equimolar ratio of 1:1 produced by MASE using the glacial acetic acid as a solvent were more soluble compared to plain drug. The dissolution rate was increased from only 59.0% of pure acyclovir up to 85.0% of ACV co-crystals within 1 hour. DSC and PXRD patterns of co-crystals were distinguished from that of individual components. The UV-spectroscopic analysis represented 62.5% of acyclovir in the co-crystals, which was directly related to the theoretical percentage of the drug and its co-former (ACV: 60.01%, TA: 39.99%). This study revealed that the optimal ratio of the ACV-TA co-crystal is 1:1, which was successfully prepared using MASE technique. This method provides a promising alternative for enhancing the solubility of acyclovir with ultimately less time and solvent consumption.

Modeling Recrystallization Kinetics Following the Dissolution of Amorphous Drugs.

Amorphous phases are frequently employed to overcome the solubility limitation that is nowadays commonplace in developmental small-molecule drugs intended for oral administration. However, since the solubility enhancement has finite longevity (it is a "kinetic solubility" effect), characterizing its duration (i.e., the so-called "parachute" effect) can be important for optimizing a formulation with regard to its in vivo exposure. Two semiempirical models, based on dispersive kinetics theory, are evaluated for their ability to precisely describe experimental transients depicting a loss in supersaturation (initially generated by the dissolution of the amorphous phase) over time, as the solubilized drug recrystallizes. It is found that in cases where the drug solubility significantly exceeds that of the crystal at longer times, the mechanism has substantial "denucleation" (dissolution) character. On the other hand, "nucleation and growth" (recrystallization) kinetics best describe systems in which the recrystallization goes to completion within the experimental time frame. Kinetic solubility profiles taken from the recent literature are modeled for the following drugs: glibenclamide, indomethacin, loratadine, and terfenadine. In the last case, a combination of three different kinetic models, two classical ones plus the dispersive model, are used together in describing the entire dissolution-recrystallization transient of the drug, obtaining a fit of R2 = 0.993. By precisely characterizing the duration of the "parachute" in vitro (e.g., under biorelevant conditions), the proposed models can be useful in predicting trends and thereby guiding formulation development and optimization.

Could the small molecules such as amino acids improve aqueous solubility and stabilize amorphous systems containing Griseofulvin?

Griseofulvin (GSF) is an antifungal drug that has low aqueous solubility and low oral bioavailability. Amorphous systems are capable to promote rapid drug dissolution, usually affording concentrations above drug solubility in the gastrointestinal tract (supersaturation) in order to promote better absorption. Thus, the aim of this work was to evaluate the ability of amino acids, as hydrophilic carriers, to improve drug kinetic solubilization and to stabilize GSF supersaturated solutions, as well as to stabilize GSF amorphous systems at solid-state. The effect of 5 amino acids on GSF precipitation behavior was investigated by solvent shift method. Amorphous systems were developed by ball milling (GSF + amino acid 1:1 M ratio) and Quench Cooling (to obtain GSF QC) techniques. The samples were characterized by solid-state techniques, submitted to in vitro kinetic solubility studies and evaluated under stability tests. Aspartic acid, methionine, valine and tryptophan demonstrated similar anti-precipitant abilities in phosphate buffer pH 6.5. However, in FaSSIF biorelevant medium, tryptophan was only one able to slow down the drug precipitation. The characterization of milled samples showed that an amorphous system was obtained just using the combination of the drug with tryptophan (GSF-TRYP BM). At the higher dose tested (0.850 mmol L−1) during in vitro kinetic solubility studies, this amorphous system increased the AUC in FaSSGF (88.6%) and FaSSIF (58.2%) media when compared to GSF QC. Thus, the ability of this amino acid to inhibit GSF precipitation appears to be dependent on its concentration in solution and could be optimized. During the stability study, TRYP inhibited GSF recrystallization in the solid-state for a period of 12 months, whereas GSF QC recrystallized in 1 week.

In vitro and in vivo toxicity evaluation of non-neuroleptic phenothiazines, antitubercular drug candidates

The phenothiazine-derived antipsychotic drugs, such as chlorpromazine and thioridazine, are bactericidal against drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis, but produce undesirable side effects at clinically relevant doses. We have previously modified four novel phenothiazines and maintained their antimycobacterial activity. This study evaluated the pharmacological and toxicity profiles of these novel non-neuroleptic phenothiazines, PTZ3, PTZ4, PTZ31 and PTZ32, for their metabolic stability, kinetic solubility and potential cytotoxic effects in vitro. To further support the safet use of these drug candidates, the in vivo pharmacological and toxicity profiles were assessed in C57BL/6 mice via single or repeated oral gavage. In acute toxicity studies, all four modified phenothiazines showed favourable safety in mice. When treated daily with 100 mg/kg of PTZ3 and PTZ4 for 2 weeks, mice displayed no signs of toxicity. Alternatively, treatment with PTZ31 resulted in 20% mortality with no toxicity evident in biochemical or histological analysis, while exposure to PTZ32 resulted in a 45% survival with increased serum concentrations of uric acid and alkaline phosphatase. The combined non-neuroleptic and antimycobacterial effects of the novel phenothiazines PTZ3, PTZ4, PTZ31 and PTZ32 demonstrated favourable pharmacological and toxicity profiles in this study, highlight the potential of these compounds as suitable anti-tuberculosis drug candidates.

Hybrid nanocrystal–amorphous solid dispersions (HyNASDs) as alternative to ASDs for enhanced release of BCS Class II drugs

A major shortcoming of drug nanocomposites as compared with amorphous solid dispersions (ASDs) is their limited supersaturation capability in dissolution media. Here, we prepared drug hybrid nanocrystal–amorphous solid dispersions (HyNASDs) and compare their performance to ASDs. A wet-milled griseofulvin (GF, BCS II drug) nanosuspension and a GF solution, both containing the same dissolved polymer–surfactant (SDS: sodium dodecyl sulfate) with 1:1 and 1:3 GF:polymer mass ratios, were spray-dried. Hydroxypropyl cellulose (HPC) and Soluplus (Sol) were used as matrix-forming polymers. XRPD, DSC, and Raman spectroscopy reveal that ASDs were formed upon spray-drying the solution-based feed, whereas nanocomposites and nanocomposites with >10% amorphous content, HyNASDs, were formed with the nanosuspension-based feed. Sol provided higher GF relative supersaturation, up to 180% and 360% for HyNASDs and ASDs, respectively, in the dissolution tests than HPC (up to 50% for both) owing to Sol’s stronger intermolecular interactions and miscibility with GF and its recrystallization inhibition. Besides the higher kinetic solubility of GF in Sol, presence of GF nanoparticles vs. micron-sized particles in the nanocomposites enabled fast supersaturation. This study demonstrates successful preparation of fast supersaturating (190% within 20 min) HyNASDs, which renders nanoparticle formulations competitive to ASDs in bioavailability enhancement of poorly soluble drugs.

Benzoxaboroles-Novel Autotaxin Inhibitors.

Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last ten years. To date, only one molecule, Ziritaxestat (GLPG1690) has entered the clinic; it is currently in Phase 3 clinical trials for idiopathic pulmonary fibrosis. Other small molecules, with different binding modes, have been investigated as ATX inhibitors for cancer including compounds possessing a boronic acid motif such as HA155. In this work, we targeted new, improved inhibitors of ATX that mimic the important interactions of boronic acid using a benzoxaborole motif as the acidic warhead. Furthermore, we aimed to improve the plasma stability of the new compounds by using a more stable core spacer than that embedded in HA155. Compounds were synthesized, evaluated for their ATX inhibitory activity and ADME properties in vitro, culminating in a new benzoxaborole compound, 37, which retains the ATX inhibition activity of HA155 but has improved ADME properties (plasma protein binding, good kinetic solubility and rat/human plasma stability).

Prediction of Bioequivalence and Food Effect Using Flux- and Solubility-Based Methods.

In this work, two different approaches have been developed to predict the food effect and the bioequivalence of marketed itraconazole (ITRA) formulations. Kinetic solubility and simultaneous dissolution-permeation tests of three (ITRA) formulations (Sporanox capsules and solution and SUBA-ITRA capsules) were carried out in simulated fasted and fed states. Fraction of dose absorbed ratios estimating food effect and bioequivalence were calculated based on these results and were compared to the in vivo study results published by Medicines Agencies. The comparison demonstrated that kinetic solubility and flux values could be used as input parameters for biopharmaceutics modeling and simulations to estimate food effect and bioequivalence. Both prediction methods were able to determine a slightly negative food effect in the case of the Sporanox solution and also a pronounced positive food effect for the Sporanox capsule. Superior bioavailability was predicted when the Sporanox solution was compared to the Sporanox capsule (in agreement with in vivo data).

Preparation of Deoxycholate-Modified Docetaxel-Cimetidine Complex Chitosan Nanoparticles to Improve Oral Bioavailability.

Docetaxel (DTX) was effective in the treatment of neoplasm but could only be administered intravenously with the poor oral bioavailability owing to its undesirable solubility, remarkably metabolic conversion, and other factors. Cimetidine (CMD), a classic CYP3A4 isozyme inhibitor, had exhibited a wide range of inhibition on the metabolism of many drugs. The aim of this study was to construct the novel docetaxel-cimetidine (DTX-CMD) complex and the chitosan-deoxycholate nanoparticles based on it to confirm whether this formulation could show advantages in terms of solubility, dissolution rate, small intestinal absorption, and oral bioavailability in comparison with the pure drug. The solid-state characterization was carried out by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), and simultaneous DSC-TGA (SDT). Dissolution rate and kinetic solubility study were determined by evaluating the amount of DTX in distilled water and phosphate buffer solution (pH = 7.4), respectively. And small intestinal absorption and pharmacokinetics study were conducted in rats. The results of this study demonstrated that we successfully constructed DTX-CMD complex and its chitosan-deoxycholate nanoparticles. Furthermore, the DTX-CMD complex increased the solubility of DTX by 2.3-fold and 2.1-fold in distilled water and phosphate buffer solution, respectively. The ultimate accumulative amount of DTX-CMD complex nanoparticles through rat small intestinal in 2h was approximately 4.9-fold and the oral bioavailability of the novel nanoparticles was enhanced 2.8-fold, compared with the pure DTX. The superior properties of the complex nanoparticles could both improve oral bioavailability and provide much more feasibility for other formulations of DTX.

Screening, crystal structures and solubility studies of a series of multidrug salt hydrates and cocrystals of fenamic acids with trimethoprim and sulfamethazine

Multidrug solids have a potential use to efficiently treat and control a superfluity of medical conditions. To address the current drawbacks of drug development in R&D, it was targeted to achieve new pharmaceutical solid forms of fenamic acids having improved solubility and thermal stability. Subsequently, five new multicomponent solids consisting of three salt hydrates of trimethoprim (TMP) with mefenamic acid (TMP-MFA-H2O), tolfenamic acid (TMP-TFA-H2O) and flufenamic acid (TMP-FFA-H2O), and two cocrystals of sulfamethazine (SFZ) with flufenamic acid (SFZ-FFA) and niflumic acid (SFZ-NFA) were prepared by liquid assisted grinding. Looking at the structures of active pharmaceutical ingredient (API) molecules, it was quite expected that a wide range of supramolecular synthons would lead to co-crystallization. New forms were characterized thoroughly by various solid-state techniques, including single crystal X-ray diffraction (SCXRD), which provided details of hydrogen bonding, molecular packing and interactions between drug and coformer. Kinetic solubility at pH 7.4 buffer study has been carried out and a comparison is made with respect to the parent drugs. A significant enhancement of NSAIDs solubility was observed in all salt hydrate systems of TMP. Thus with increasing physicochemical properties such as improved solubility further leads to the enhancement of bioavailability, which has implications to overcoming the formulation related problems of active pharmaceutical ingredients (APIs).

Five Solid Forms of a Potent Imidazopyridazine Antimalarial Drug Lead: A Preformulation Study

A novel antimalarial drug lead, 6-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-imidazo[1,2-b]pyridazine (MMV652103), with good in vitro and in vivo antiplasmodial effects but poor aqueous solubility was investigated for preformulation beneficiation by supramolecular methods. Three polymorphs (Forms 1–3), an amorphous phase (Form 4), and a monohydrate (Form 5) were discovered and characterized by thermal analytical methods including hot stage microscopy, differential scanning calorimetry, and thermogravimetric analysis, complemented by variable-temperature powder X-ray diffraction. Single crystals of polymorphic Form 1, Form 2, and a monohydrate of the drug lead were isolated, and their structures were elucidated by X-ray diffraction, which enabled the respective molecular conformations, inter- and intramolecular interactions, and packing arrangements to be determined. A schematic energy–temperature diagram incorporating the polymorphic forms and the amorphous form of the drug lead was constructed using data gleaned from thermal analysis, kinetic solubility experiments, and observations of solvent-mediated transitions. The amorphous form of the drug lead displayed a significant increase in dissolution rate, yielding a maximum concentration of 3–4 times those of the crystalline forms after 1 h.

An investigation of the inter-molecular interaction, solid-state properties and dissolution properties of mixed copovidone hot-melt extruded solid dispersions

Previous research has focused on spray dried quaternary mixtures which, due to the addition of a surfactant, affected the physical stability and amorphous stability of selected model drugs. Very little research has focused on how inter-molecular interactions play a role in the successful formulation of hot-melt extruded quaternary amorphous blends and how they affect physical stability and solubility of amorphous solid dispersions (ASDs). Therefore the aim of this study was to investigate the role of inter-molecular interactions and their effect on the solid-state and dissolution properties of mixed copovidone amorphous solid dispersions (ASDs). The polymeric copovidone carriers used in this study were Poly (vinylpyrrolidone-vinyl acetate copolymer) and Plasdone S-630 (PL-S630) which in terms of monographs are the same, however they have different solid-state and dissolution properties. The ASDs showed a significantly higher dissolution rate compared to amorphous and pure INM in pH buffer 1.2 with a kinetic solubility of 24 μg/ml. The stability data showed that INM remained amorphous in solid solutions with PVP VA64 and Plasdone S-630, except for the higher drug loads. It was concluded that % drug loading did have a significant effect on the solubility of INM due to recrystallization at higher drug loads.

Maximum Loaded Amorphous Azithromycin Produced Using the Wetness Impregnation Method with Fractional Steps for Dermal Prophylaxis Against Lyme Disease.

Azithromycin was loaded onto the μm-sized mesoporous silica Davisil® SP53D-11920 using the wetness impregnation method with fractional steps (WIFS) and further incorporated into a 5 % hydroxypropyl cellulose gel to prevent Lyme disease. Maximum loadings (32.0 % w/w and 33.2 % w/w) were produced by different concentrated loading solutions and determined by X-ray diffraction (XRD). A total of 24 months stability of the amorphous azithromycin state in the silica (33.2 % loading) and 18 months stability in the gel (33.2 % loading) at 4 °C were also confirmed by XRD. The higher kinetic solubility at 40 min (1,300 μg/mL versus 93 μg/mL) and higher porcine ear skin penetration compared to the raw drug powder indicated higher dermal bioavailability of the azithromycin-loaded silica (32.0 % loading), even when compared to the "gold standard" nanocrystals and another clinical effective azithromycin formulation with ethanol. In summary, maximum loaded silicas with azithromycin by WIFS is a promising dermal formulation for prophylaxis against Lyme disease.

Predictive models of aqueous solubility of organic compounds built on A large dataset of high integrity

Aqueous solubility is one of the most important properties in drug discovery, as it has profound impact on various drug properties, including biological activity, pharmacokinetics (PK), toxicity, and in vivo efficacy. Both kinetic and thermodynamic solubilities are determined during different stages of drug discovery and development. Since kinetic solubility is more relevant in preclinical drug discovery research, especially during the structure optimization process, we have developed predictive models for kinetic solubility with in-house data generated from 11,780 compounds collected from over 200 NCATS intramural research projects. This represents one of the largest kinetic solubility datasets of high quality and integrity. Based on the customized atom type descriptors, the support vector classification (SVC) models were trained on 80% of the whole dataset, and exhibited high predictive performance for estimating the solubility of the remaining 20% compounds within the test set. The values of the area under the receiver operating characteristic curve (AUC-ROC) for the compounds in the test sets reached 0.93 and 0.91, when the threshold for insoluble compounds was set to 10 and 50 μg/mL respectively. The predictive models of aqueous solubility can be used to identify insoluble compounds in drug discovery pipeline, provide design ideas for improving solubility by analyzing the atom types associated with poor solubility and prioritize compound libraries to be purchased or synthesized.

A comprehensive kinetic and thermodynamic study of CO2 absorption in blends of monoethanolamine and potassium lysinate: Experimental and modeling

In this work, a kinetic and thermodynamic study of CO2 absorption in blends of monoethanolamine (MEA) and potassium lysinate (K-Lys) solutions was carried out at low CO2 partial pressures and temperatures (303–323 K). The CO2 loading capacity, density and viscosity of MEA + K-Lys solutions were measured. A modified Kent-Eisenberg model was applied to predict the CO2 loading capacity and also to determine the reaction equilibrium constants for the MEA + K-Lys system. The results showed that the model predictions are in excellent agreement with the experimental data. In order to study the reaction kinetics between CO2 and the MEA + K-Lys solution, the values of the reaction rate constant, the overall reaction kinetic constant, reaction order, physical solubility and CO2 diffusivity were determined. Finally, the absorption performance of the MEA + K-Lys system was compared with other common CO2 absorbents in terms of absorption heat, CO2 loading capacity and absorption rate. It was found that MEA + K-Lys has a better performance compared to other absorbents which makes it an attractive alternative to alkanolamines for CO2 capture.

Assessment of Biopharmaceutical Performance of Supersaturating Formulations of Carbamazepine in Rats Using Physiologically Based Pharmacokinetic Modeling.

There is an overgrowing emphasis on supersaturating drug delivery systems (SDDS) with increase in number of poorly water-soluble compounds. However, biopharmaceutical performance from these formulations is limited by phase transformation to stable crystalline form due to their high-energy physical form. In the present study, in vitro kinetic solubility in water and dissolution in biorelevant medium integrated with in silico physiologically based pharmacokinetic (PBPK) modeling was used to predict biopharmaceutical performance of SDDS of poorly water-soluble compound, carbamazepine (CBZ). GastroPlus™ with advanced compartmental absorption and transit model was used as a simulation tool for the study. Wherein, the model was developed using physicochemical properties of CBZ and disposition parameters obtained after intravenous administration of CBZ (20mg/kg) into Sprague-Dawley (SD) rats. Biorelevant medium was selected by screening different dissolution media for their capability to predict oral plasma concentration-time profile of marketed formulation of CBZ. In vivo performance of SDDS was predicted with the developed model and compared to observed plasma concentration-time profile obtained after oral administration of SDDS into SD rats (20mg/kg). The predictions, with strategy of using kinetic solubility and dissolution in the selected biorelevant medium, were consistent with observed biopharmaceutical performance of SDDS. Additionally, phase transformation of CBZ during gastrointestinal transit of formulations was evaluated and correlated with in vivo dissolution deconvoluted by Loo-Reigelman analysis.

Perspectives in solubility measurement and interpretation.

Several key topics in solubility measurement and interpretation are briefly summarized and illustrated with case studies drawing on published solubility determinations as a function of pH. Featured are examples of ionizable molecules that exhibit solubility-pH curve distortion from that predicted by the traditionally used Henderson-Hasselbalch equation and possible interpretations for these distortions are provided. The scope is not exhaustive; rather it is focused on detailed descriptions of a few cases. Topics discussed are limitations of kinetic solubility, ‘brick-dust and grease-balls,’ applications of simulated and human intestinal fluids, supersaturation and the relevance of pre-nucleation clusters and sub-micellar aggregates in the formation of solids, drug-buffer/excipient complexation, hydrotropic solubilization, acid-base ‘supersolubilization,’ cocrystal route to supersaturation, as well as data quality assessment and solubility prediction. The goal is to highlight principles of solution equilibria – graphically more than mathematically – that could invite better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids. The value of solid state characterizations is stressed but not covered explicitly in this mini-review.

Which Parameter is Governing for Aqueous Redox Flow Batteries with Organic Active Material?

AbstractA multitude of factors contribute to the performance of redox flow batteries with organic active material. In this work, experimental and theoretical methods are elucidated to give information about the most important of these: redox potential, kinetic rate constant, diffusion constant, and solubility. They are found to be highly interdependent – especially for different solvents. By implication, novel organic active materials have to be analyzed jointly by chemists, materials scientists, and by reaction and process engineers to propel the redox flow battery as future energy storage device.

Structure\u2013activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines

BackgroundMalaria is one of the most prevalent tropical infectious diseases. Since recently cases of artemisinin resistance were reported, novel anti-malarial drugs are required which differ from artemisinins in structure and biological target. The plasmodial glycogen synthase kinase-3 (PfGSK-3) was suggested as a new anti-malarial drug target. 4-Phenylthieno[2,3-b]pyridines were previously identified as selective PfGSK-3 inhibitors with antiplasmodial activity. The present study aims at identifying a molecular position on this scaffold for the attachment of side chains in order to improve solubility and antiplasmodial activity. Furthermore, the role of axial chirality in the compound class for antiplasmodial activity and PfGSK-3 inhibition was investigated.Methods4-Phenylthieno[2,3-b]pyridines with substituents in 4-position of the phenyl ring were docked into the ATP binding site of PfGSK-3. The compounds were synthesized employing a Thorpe reaction as final step. The enantiomers of one congener were separated by chiral HPLC. All derivatives were tested for inhibition of asexual erythrocytic stages of transgenic NF54-luc Plasmodium falciparum. Selected compounds with promising antiplasmodial activity were further evaluated for inhibition of HEK293 cells as well as inhibition of isolated PfGSK-3 and HsGSK-3. The kinetic aqueous solubility was assessed by laser nephelometry.ResultsThe para position at the 4-phenyl ring of the title compounds was identified as a suitable point for the attachment of side chains. While alkoxy substituents in this position led to decreased antiplasmodial activity, alkylamino groups retained antiparasitic potency. The most promising of these congeners (4h) was investigated in detail. This compound is a selective PfGSK-3 inhibitor (versus the human GSK-3 orthologue), and exhibits improved antiplasmodial activity in vitro as well as better solubility in aqueous media than its unsubstituted parent structure. The derivative 4b was separated into the atropisomers, and it was shown that the (+)-enantiomer acts as eutomer.ConclusionsThe attachment of alkylamino side chains leads to the improvement of antiplasmodial activity and aqueous solubility of selective PfGSK-inhibitors belonging to the class of 4-phenylthieno[2,3-b]pyridines. These molecules show axial chirality, a feature of high impact for biological activity. The findings can be exploited for the development of improved selective PfGSK-3 inhibitors.