Lipophilicity Parameters Research Articles

SEPARATION OF POLYMETOXYLATED FLAVONE FROM CITRUS FRUIT FLAVEDO EXTRACTS UNDER “MONOMERIC” REVERSE PHASE HPLC CONDITIONS

For the first time, the regularities of retention of six polymethoxylated flavones from orange peel were determined under reversed-phase chromatography on “monomeric” C18 stationary phases. These flavonoids have received recent attention as compounds with unique biological activities, including (supposedly) effects on the development of intractable Alzheimer's and Parkinson's diseases. Sinensetin (3′,4′,5,6,7-pentamethoxyflavone), 3′,4′,3,5,6,7-hexamethoxyflavone, nobiletin (3′,4′,5,6,7,8-hexamethoxyflavone), 4′,5,6,7-tetramethoxyflavone, 3′,4′,3,5,6,7,8-heptamethoxyflavone and tangeretin (4′,5,6,7,8-pentamethoxyflavone) were found in orange flavedo extract. In the HPLC-friendly retention range (approximately retention factors from 2 to 20), the elution order of the six flavones mentioned above was found to remain unchanged for a number of different trademarks of stationary phases. The largest, but not critical, changes in retention order were found when using a column with increased activity of residual silanol groups. This allows for peak assignments taking into account literature data. Attention was drawn to the fact that the addition of a methoxy group to the structure of the flavone molecule at positions 3 and 8 leads to an increase in retention, while an unusual increase in retention is observed when a methoxy group is removed from position 3′ in the presence of another methoxy group at position 4′. In this case, the addition of methoxy groups both to positions 3 and 8, and to 3′ is accompanied by a bathochromic shift in the absorption maximum of band I, despite the fact that the electron transition in this case is localized on rings B and C. It has been shown that the use of lipophilicity parameters, logP, which can be calculated using several programs, provides results that can be used with caution when predicting the retention of polymethoxyflavones under reversed-phase HPLC conditions, since not all experimental relationships correlate with the calculated logP. For citation: Oleinits E.Yu., Deineka V.I., Pronin I.S., Deineka L.A. Separation of polymetoxylated flavone from citrus fruit flavedo extracts under “monomeric” reverse phase HPLC conditions. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 12. P. 25-32. DOI: 10.6060/ivkkt.20246712.7057.

Aniline Derivatives Containing 1-Substituted 1,2,3-Triazole System as Potential Drug Candidates: Pharmacokinetic Profile Prediction, Lipophilicity Analysis Using Experimental and In Silico Studies.

Background: The triazole ring is an attractive structural unit in medicinal chemistry, and chemical compounds containing this type of system in their structure exhibit a wide spectrum of biological activity. They are used in the development of new pharmaceuticals. One of the basic parameters considered in the initial phase of designing potential drugs is lipophilicity, which affects the bioavailability and pharmacokinetics of drugs. Methods: The study aimed to assess the lipophilicity of fifteen new triazole derivatives of aniline using reversed phase thin layer chromatography (RP-TLC) and free web servers. Based on in silico methods, the drug similarity and pharmacokinetic profile (ADMET) of synthesized molecules were assessed. Results: A relationship was observed between the structure of the title compound, including the position of substitution in the aniline ring, and the experimental values of lipophilicity parameters (logPTLC). Most of the algorithms used to determine theoretical logP values showed less sensitivity to structural differences of the tested molecules. All obtained derivatives satisfy the drug similarity rules formulated by Lipinski, Ghose and Veber. Moreover, in silico analysis of the ADME profile showed favorable values of parameters related to absorption.

Rapid Iodination Kinetic Studies of o-Toluidine in Aqueous Medium: A Pharmacokinetic Insight from QSAR and Molecular Docking of its Iodo Product with Cytochrome P450

The kinetic data of uncatalyzed rapid iodination of o-toluidine using molecular iodine in aqueous medium was investigated by employing hydrodynamic voltammetry (HV) technique. The frequency factor, activation energy and entropy change accompanying the reaction were evaluated. The reaction followed second order kinetics that had a half-life of 90 s and specific reaction rate 888.87 M s–1 at 22.1 ºC. The iodo product was formed via the green route in the aqueous solvent. The physico-chemical characteristics, lipophilicity, water solubility and pharmacokinetic parameters were derived by QSAR analysis. The docking of the iodo product with cytochrome P450 exhibited steric and physiological complementarity of the ligand-protein interface through hydrogen bonding and pi-pi stacking interactions, indicating that the product exhibited metabolic activity was similar to the existing drugs.

Analysis of Lipophilicity and Pharmacokinetic Parameters of Dipyridothiazine Dimers with Anticancer Potency.

Lipophilicity is an essential parameter of a compound that determines the solubility and pharmacokinetic properties that determine the transport of the drug to the molecular target. Dimers of dipyridothiazines are diazaphenothiazine derivatives exhibiting diverse anticancer potential in vitro, which is related to their affinity for histone deacetylase. In this study, the lipophilicity of 16 isomeric dipyridothiazine dimers was investigated theoretically and experimentally by reversed-phase thin-layer chromatography (RP-TLC) in an acetone-TRIS buffer (pH = 7.4). The relative lipophilicity parameter RM0 and specific hydrophobic surface area b were significantly intercorrelated, showing congeneric classes of dimers. The parameter RM0 was transformed into parameter logPTLC by use of the calibration curve. Molecular descriptors, ADMET parameters and probable molecular targets were determined in silico for analysis of the pharmacokinetic profile of the tested compounds showing anticancer activity. The analyzed compounds were tested in the context of Lipinski's rule of five, Ghose's rule and Veber's rule, confirming their bioavailability.

Immobilised artificial membrane liquid chromatography vs liposome electrokinetic capillary chromatography: Suitability in drug/bio membrane partitioning studies and effectiveness in the assessment of the passage of drugs through the respiratory mucosa

This study pioneers a comparison of the application of biomimetic techniques, immobilised artificial membrane liquid chromatography (IAM LC) and liposome electrokinetic capillary chromatography (LEKC), for the prediction of pulmonary drug permeability. The pulmonary absorption profiles of 26 structurally unrelated drug-like molecules were evaluated using their IAM hydrophobicity index (CHI IAM) measured in IAM LC, and the logarithm of distribution constants (log KLEKC) derived from the LEKC experiments. Lipophilicity (phospholipids) parameters obtained from IAM LC and most LEKC analyses were linearly related to the n-octanol/water partitioning coefficients of the neutral forms (i.e., log Po/w values) to a moderate extent. However, the relationship with distribution coefficients at the experimental pH (7.4) (i.e., log D7.4) were weaker overall for IAM LC data and sigmoidal for some liposome compositions (phosphatidyl choline (PC): phosphatidyl inositol (PI) 85:15 mol% and 90:10 mol%) and concentrations (4 mM) in LEKC. This suggests that phospholipid partitioning supports both hydrophobic and electrostatic interactions occurring between ionised drugs and charged phospholipid moieties. The latter interactions are original when compared to those taking place in the more established n-octanol/water partitioning systems.A stronger correlation (R2 > 0.65) was identified between the LEKC retention parameters, and the experimental apparent lung permeability (i.e., log Papp values) as opposed to the values obtained by IAM LC. Therefore, LEKC offers unprecedented advantages over IAM LC in simulating cell membrane partitioning processes in the pulmonary delivery of drugs. Although LEKC has the advantage of more effectively simulating the electrostatic and hydrophobic forces in drug/pulmonary membrane interactions in vitro, the technique is unsuitable for analysing highly hydrophilic neutral or anionic compounds at the experimental pH. Conversely, IAM LC is useful for analysing compounds spanning a wider range of lipophilicity. Its simpler and more robust implementation, and propensity for high-throughput automation make it a favourable choice for researchers in drug development and pharmacological studies.

Study of the Lipophilicity and ADMET Parameters of New Anticancer Diquinothiazines with Pharmacophore Substituents.

Lipophilicity is one of the principal parameters that describe the pharmacokinetic behavior of a drug, including its absorption, distribution, metabolism, elimination, and toxicity. In this study, the lipophilicity and other physicochemical, pharmacokinetic, and toxicity properties that affect the bioavailability of newly synthesized dialkylaminoalkyldiquinothiazine hybrids as potential drug candidates are presented. The lipophilicity, as RM0, was determined experimentally by the RP-TLC method using RP18 plates and acetone-TRIS buffer (pH 7.4) as the mobile phase. The chromatographic parameters of lipophilicity were compared to computationally calculated partition coefficients obtained by various types of programs such as iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, LogP, logP, and milogP. In addition, the selected ADMET parameters were determined in silico using the SwissADME and pkCSM platforms and correlated with the experimental lipophilicity descriptors. The results of the lipophilicity study confirm that the applied algorithms can be useful for the rapid prediction of logP values during the first stage of study of the examined drug candidates. Of all the algorithms used, the biggest similarity to the chromatographic value (RM0) for certain compounds was seen with iLogP. It was found that both the SwissADME and pkCSM web tools are good sources of a wide range of ADMET parameters that describe the pharmacokinetic profiles of the studied compounds and can be fast and low-cost tools in the evaluation of examined drug candidates during the early stages of the development process.

The chromatographic determination of the lipophilicity of newly synthesized aromatic-heterocyclic carbohydrazone derivatives with potential antibacterial and antituberculosis activities

Hydrazones are a large group of compounds with antibacterial, antituberculosis, antifungal, anticonvulsant, antiviral, antiprotozoal, anticancer and anti-inflammatory properties. Ten newly synthesized hydrazones were tested for their antimicrobial and antituberculosis activities. Screening tests were performed using the disk diffusion method. Then, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration were determined for the most promising compounds. Synergy of the action of the tested substances with reference drugs was also tested. Drugs standardly used in the treatment of tuberculosis: rifampicin and isoniazid were used as reference substances. Based on the obtained results, fractional inhibitory concentration coefficients were calculated for individual combinations. The tested ones showed weak antimicrobial activity. They didn’t show either synergism of action with rifampicin and isoniazid. Then, experimental and theoretical lipophilicity parameters were determined for the obtained derivatives. The research was carried out using reversed-phase high-performance liquid chromatography (RP-HPLC), in which the mobile phase is a mixture of methanol and water. To confirm the validity of the chromatographic technique used, both experimental and calculated lipophilicity parameters were correlated. The correlation matrix of these relationships was subjected to principal component analysis (PCA).

Comparison of HPLC, HPTLC, and In Silico Lipophilicity Parameters Determined for 5-Heterocyclic 2-(2,4-Dihydroxyphenyl)-1,3,4-thiadiazoles.

The 5-heterocyclic 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles were obtained as potential biologically active compounds. Lipophilicity is one of the most important physicochemical properties of compounds and was already taken into account during the drug candidates design and development. The lipophilicity of compounds was determined using the computational (log P) and chromatography (log kw, RMw) methods. The experimental ones included the reverse-phase column high performance liquid chromatography RP (HPLC) with C8, C18, phosphatidylcholine (IAM), and cholesterol stationary phases and the thin layer chromatography (RP-HPTLC) with C8 and C18 stationary phases and various organic modifiers under the isocratic conditions. Descriptive statistics, correlation, and PCA analyses were used to compare the obtained results. For lipophilicity estimation of the tested compounds by HPTLC, dioxane and MeOH seem to be particularly beneficial as organic modifiers. The chromatographic lipophilicity parameters log kw (RMw) were well correlated and highly redundant (85%) compared with those calculated. Most compounds possess lipophilicity parameters within the recommended range for drug candidates.

Reversed-phase thin-layer chromatography and ultra-performance liquid chromatography/mass spectrometry to estimate the drug likeness of phosphodiesterase 10A inhibitors with phthalimide core

Lipophilicity is a physicochemical parameter well known as a decisive factor for predicting the successful development of a drug. Thus, a balance between potency and physicochemical properties during medicinal chemistry optimization is needed. In this study, the lipophilicity of isoindole-1,3(2H)-dione derivatives designed as phosphodiesterase 10A (PDE10A) inhibitors was determined by chromatographic [reversed-phase thin-layer chromatography (RP-TLC) and ultra-performance liquid chromatography/mass spectrometry (UPLC/MS)] and in silico methods. To assess the correlation between the obtained lipophilicity parameters, principal component analysis (PCA) was performed. logP values obtained by chromatographic (logPRP-TLC and logPUPLC/MS) and in silico methods were compared using the PCA method. The results of PCA revealed that logPUPLC/MS and in silico clogP provided by the ChemDraw program were highly correlated. Compounds’ drug likeness was screened, and the pharmacokinetic properties were predicted. All the investigated compounds displayed drug-likeness properties, and they met the criteria of Lipinski’s rule of five, which predicted the oral bioavailability of drug candidates. Analysis of the influence of physicochemical properties on the biological activity showed that the compounds with increased potency on PDE10A had significantly higher topological polar surface area (TPSA) values. The blood‒brain barrier permeability and the hemolytic activity of model compound 18 were examined. The model compound 18 displayed no toxicity effect on erythrocytes in the hemolytic assay and good parallel artificial membrane permeability. The results showed that phthalimide compounds with benzimidazole moiety are a source of compound-targeted inhibition of PDE10A with balanced physicochemical and drug-likeness properties.

QSRR modeling of lipophilicity of new spirohydantoin derivatives determined with various TLC systems.

A Quantitative structure-retention relationship (QSRR) analysis has been carried out on the chromatography parameters of lipophilicity of selected spirohydantoins. Multiple linear regression (MLR) was applied for construct the QSRR models. The chromatographic parameters of lipophilicity were determined by reversed-phase thin-layer chromatography. Chromatographic analyses were performed on C-18 modified silica gel with a two-component mobile phase consisting of water and protic organic solvent (ethanol, n-propanol, i-propanol, or t-butanol) in different ratios. QSRR models were built and for additional four aqueous mobile phases: acetone-water, acetonitrile-water, tetrahydrofuran-water, and 1,4-dioxane-water (results published before). In total, chromatographic lipophilicity parameters obtained for two types of organic solvents was subject of the QSRR. The predictive ability of each model was defined by an internal validation coefficient. The best QSRR model for predicting the chromatographic parameter of lipophilicity was obtained for tetrahydrofuran as an organic solvent.

Evaluation of lipophilicity and drug-likeness of donepezil-like compounds using reversed-phase thin-layer chromatography.

Fourteen donepezil-like acetylcholinesterase (AChE) inhibitors from our library were analyzed using reversed-phase thin-layer chromatography to assess their lipophilicity and blood-brain barrier permeability. Compounds possessed N-benzylpiperidine and N,N-diarylpiperazine moieties connected via a short carboxamide or amine linker. Retention parameters RM 0, b, and C0 were considered as the measures of lipophilicity. Besides, logD of the investigated compounds was determined chromatographically using standard compounds with known logPow and logD values at pH 11. Experimentally obtained lipophilicity parameters correlated well with in silico generated results, and the effect of the nature of the linker between two pharmacophores and substituents on the arylpiperazine part of the molecule was observed. As a result of drug-likeness analysis, both Lipinski's rule of five and Veber's rule parameters were determined, suggesting that examined compounds could be potential candidates for further drug development. Principal component analysis was performed to obtain an insight into a grouping of compounds based on calculated structural descriptors, experimentally obtained values of lipophilicity, and AChE inhibitory activity.

Heterocycles 52: The Drug-Likeness Analysis of Anti-Inflammatory Thiazolo[3,2-b][1,2,4]triazole and Imidazo[2,1-b][1,3,4]thiadiazole Derivatives.

Lipophilicity, a significant physicochemical parameter of bioactive molecules, along with absorption, distribution, metabolism, excretion parameters and toxicity risk, was investigated for 32 thiazolo[3,2-b][1,2,4]triazole and imidazo[2,1-b][1,3,4]thiadiazole derivatives with anti-inflammatory potential. The experimental lipophilicity study was carried out by reversed-phase thin-layer chromatography in a binary isopropanol-water mobile phase, and the obtained results were compared with the theoretical lipophilicity parameters estimated by various computational methods. Strong correlations were found between the experimental retention factors and calculated partition coefficients. A modified Petra/Osiris/Molinspiration analysis was performed on the previously synthesized compounds, using SwissADME, Osiris and Molinspiration web tools. The predicted in silico parameters highlighted the most promising compounds as potential drug candidates. The compounds showed good gastrointestinal absorption, moderate activity according to the bioactivity score (values situated between -1.25 and -0.06), and a safe toxicity profile. The results obtained in this study will contribute to lipophilicity studies and other future studies focused on modulating new drug candidates starting from thiazolo[3,2-b][1,2,4]triazole and imidazo[2,1-b][1,3,4]thiadiazole derivatives, which are important heterocycles in medicinal chemistry.

Antibacterial Activity and Mechanisms of Plant Flavonoids against Gram-Negative Bacteria Based on the Antibacterial Statistical Model.

The antimicrobial quantitative structure-activity relationship of plant flavonoids against Gram-positive bacteria was established in our previous works, and the cell membrane was confirmed as a major site of action. To investigate whether plant flavonoids have similar antibacterial effects and mechanisms against both Gram-negative and Gram-positive bacteria, here, the minimum inhibitory concentrations (MICs) of 37 plant flavonoids against Escherichia coli were determined using the microdilution broth method, and then the correlation between their lipophilic parameter ACD/LogP or LogD7.40 value and their MIC was analyzed. Simultaneously, the correlation between the ACD/LogP or LogD7.40 value and the MIC of 46 plant flavonoids reported in the literature against E. coli was also analyzed. Both sets of results showed that there is a significant correlation between the LogP value and the MIC of plant flavonoids against Gram-negative bacteria. However, it is difficult to effectively predict the MIC of plant flavonoids against Gram-negative bacteria from their lipophilic parameters. By comparing two regression curves derived from plant flavonoids against Gram-negative and Gram-positive bacteria, it was further discovered that the antibacterial activities of most plant flavonoids against Gram-negative bacteria are stronger than those against Gram-positive bacteria when their LogP values are less than approximately 3.0, but the opposite is true when their LogP values are more than approximately 3.6. Moreover, this comparison also suggests that unlike mainly acting on the cell membrane of Gram-positive bacteria, plant flavonoids have multiple mechanisms against Gram-negative species, while the cell membrane is also an important action site among them. Combined with the correlation analyses between the enzyme inhibitory activity and the LogP value of the reported flavonoids, it was further suggested that DNA gyrase is another important target of plant flavonoids against Gram-negative bacteria.

Partition coefficient of gamavuton-0 in different organic solvents and pH: Experimental study

Gamavuton-0 (GVT-0) is a derivative of curcumin that is reported to have acted as a biological activity, such as anticancer, antioxidant, and anti-inflammation. As a new drug compound, a hydrophobic or lipophilic parameter like coefficient partition should be determined to study the penetration ability of the compound to the body's biological membranes. This study aims to determine the effectiveness of re-maceration on the purification of GVT-0, before the partition coefficient values determination of GVT-0, and determine the effect of pH and polarity index of organic solvent on the partition coefficient. This study was conducted in four stages: synthesis, purification, analysis of the purity, and partition coefficient determination. The partition coefficient of GVT-0 was conducted at different pH (ranging from 2 to 8) and two different organic solvents with different polarity indexes at the temperature of 37 °C. Synthesis was done by reaction between acetone and vanillin in the round bottle flask, as the reaction chamber was equipped with a water condenser. The purification process was carried out by the re-maceration method using hot distilled water. Then, purity was determined using Thin Layer Chromatography (TLC), melting point analysis, and FTIR. The determination of the partition coefficient was done using the shake flask method. The organic solvent used was chloroform and toluene. The purity analysis using TLC, melting point test, and FTIR proved that the GVT-0 compound used in this work is pure. These results show that pH affects the partition coefficient value. The partition coefficient increases from pH 2 to 4 and decreases from pH 6 to 8. The highest partition coefficient value is obtained at around pH 4–5 compared to pH 2 and 8. Also, the different solvents with different polarity indexes give different values of partition coefficient partition; a higher partition coefficient value was for a higher polarity solvent.

Evaluation of the Usefulness of Topological Indices for Predicting Selected Physicochemical Properties of Bioactive Substances with Anti-Androgenic and Hypouricemic Activity.

Due to the observed increase in the importance of computational methods in determining selected physicochemical parameters of biologically active compounds that are key to understanding their ADME/T profile, such as lipophilicity, there is a great need to work on accurate and precise in silico models based on some structural descriptors, such as topological indices for predicting lipophilicity of certain anti-androgenic and hypouricemic agents and their derivatives, for which the experimental lipophilicity parameter is not accurately described in the available literature, e.g., febuxostat, oxypurinol, ailanthone, abiraterone and teriflunomide. Therefore, the following topological indices were accurately calculated in this paper: Gutman (M, Mν), Randić (0χ, 1χ, 0χν, 1χν), Wiener (W), Rouvray-Crafford (R) and Pyka (A, 0B, 1B) for the selected anti-androgenic drugs (abiraterone, bicalutamide, flutamide, nilutamide, leflunomide, teriflunomide, ailanthone) and some hypouricemic compounds (allopurinol, oxypurinol, febuxostat). Linear regression analysis was used to create simple linear correlations between the newly calculated topological indices and some physicochemical parameters, including lipophilicity descriptors of the tested compounds (previously obtained by TLC and theoretical methods). Our studies confirmed the usefulness of the obtained linear regression equations based on topological indices to predict ADME/T important parameters, such as lipophilicity descriptors of tested compounds with anti-androgenic and hypouricemic effects. The proposed calculation method based on topological indices is fast, easy to use and avoids valuable and lengthy laboratory experiments required in the case of experimental ADME/T studies.

Lipophilic Studies and In Silico ADME Profiling of Biologically Active 2-Aminothiazol-4(5H)-one Derivatives.

Pseudothiohydantoin derivatives have a wide range of biological activities and are widely used in the development of new pharmaceuticals. Lipophilicity is a basic, but very important parameter in the design of potential drugs, as it determines solubility in lipids, nonpolar solvents, and makes it possible to predict the ADME profile. The aim of this study was to evaluate the lipophilicity of 28 pseudothiohydantoin derivatives showing the inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) using chromatographic methods. Experimentally, lipophilicity was determined by reverse phase thin layer chromatography (RP-TLC) and reverse phase high-performance liquid chromatography (RP-HPLC). In both methods, methanol was used as the organic modifier of the mobile phase. For each 2-aminothiazol-4(5H)-one derivative, a relationship was observed between the structure of the compound and the values of the lipophilicity parameters (log kw, RM0). Experimental lipophilicity values were compared with computer calculated partition coefficient (logP) values. A total of 27 of the 28 tested compounds had a lipophilicity value < 5, which therefore met the condition of Lipinski's rule. In addition, the in silico ADME assay showed favorable absorption, distribution, metabolism, and excretion parameters for most of the pseudothiohydantoin derivatives tested. The study of lipophilicity and the ADME analysis indicate that the tested compounds are good potential drug candidates.

Synthesis, Spectroscopic Analysis, Molecular Docking, Molecular Dynamics Simulation of 5-(Adamantan-1-yl)-4-(3-Chlorophenyl)-2,4-Dihydro-3H-1,2,4-Triazole-3-Thione, a Potential Anti-proliferative Agent

We report the synthesis, spectroscopic properties, and anti-proliferative efficacy of the adamantane-linked 1,2,4-triazole derivative 5-(adamantan-1-yl)-4-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione. Crystal packing and intermolecular interactions have been quantified using Hirshfeld surfaces and two-dimensional fingerprint plots. ADMET characteristics, bioavailability, and drug-likeness define the compound’s bioactivity. The gastrointestinal absorption is anticipated to be high, and the projected bioavailability score is 0.55. The topological polar surface area and iLOGP, XLOGP, WLOGP, and MLOGP lipophilicity parameters have been calculated to be 65.70 Å2, 3.24, 4.74, 5.05, and 4.07, respectively. To investigate 5A4ClT's EGFR inhibition and its use in the treatment of non-small cell lung cancer, Autodock Vina was used to dock it with the crystal structure of the EGFR kinase domain protein. The title chemical hydrophobically interacts with the receptor residues LEU718, VAL726, ALA743, GLU762, THR790, LEU792, MET793, GLY796, ARG841, ASN842, and LEU844 and forms hydrogen bonds with ASP855 and THR854 with an affinity of −8.3 kcal/mol. Toxicity end points and comparison with NSCLC drugs yielded promising findings. 120 ns molecular dynamics simulations confirmed the ligand’s dynamic stability in the target protein’s binding pocket. This research lays the groundwork for future in vivo investigations of 5A4ClT as a non-small cell lung cancer therapy.

Study on binding affinity profile, bioactivity, and lipophilicity of selected antipsychotic drugs

Schizophrenia is a complex mental illness that affects almost 1% of the population and has no curative treatment. Currently, available neuroleptic drugs have severe limitations and induce drug-related adverse effects. Receptor binding affinity parameters and lipophilicity are important characteristics that describe the bioactivity of these drugs. Lipophilicity is an important physicochemical property of a drug, which predicts distribution, binding to plasma protein, crossing the blood–brain barrier, and biological activity. Five antipsychotic drugs (Haloperidol, Risperidone, Aripiprazole, Olanzapine, and Quetiapine) were selected and the experimental determination of lipophilicity was carried out by reverse phase thin-layer chromatography (RP-TLC) using four types of stationary phases (RP-18, CN, Diol, and NH2 modified silica gel HPTLC plates) and acetonitrile-water with increasing percentage of acetonitrile and 0.2% formic acid in each case as mobile phase. Lipophilicity parameters (mRM and RM0) calculated from the experimental chromatographic retention data were discussed in terms of the correlation with different receptor binding affinity parameters determined by computational methods.

In silico evaluation of pharmacokinetics properties of withanolides and simulation of their biological activities against Alzheimer’s disease

The withanolides are naturally occurring steroidal lactones found mainly in plants of the Solanaceae family. The subtribe Withaninae includes species like Withania sominifera, which are a source of many bioactive withanolides. In this work, we selected and evaluate the ADMET-related properties of 91 withanolides found in species of the subtribe Withaninae computationally, to predict the relationship between their structures and their pharmacokinetic profiles. We also evaluated the interaction of these withanolides with known targets of Alzheimer’s disease (AD) through molecular docking and molecular dynamics. Withanolides presented favorable pharmacokinetic properties, like high gastrointestinal absorption, lipophilicity (logP ≤ 5), good distribution and excretion parameters, and a favorable toxicity profile. The specie Withania aristata stood out as an interesting source of the promising withanolides classified as 5-ene with 16-ene or 17-ene. These withanolides presented a favourable pharmacokinetic profile and were also highlighted as the best candidates for inhibition of AD-related targets. Our results also suggest that withanolides are likely to act as cholinesterase inhibitors by interacting with the catalytic pocket in an energy favorable and stable way. Communicated by Ramaswamy H. Sarma

Methodology for determining the residual content of active ingredients of agrochemicals in surface waters

Agricultural water bodies are multifunctional objects in the agricultural production cycle. Residual amounts of the active ingredients of pesticide agrochemicals can enter and contaminate a water body during some agro-technological tasks. The purpose of this study was to investigate the conditions for the extraction of residual amounts of xenobiotics from surface water containing suspended particles and to measure their content by chromatographic methods. To determine the optimal conditions for the extraction of target xenobiotics, the values of the lipophilicity parameters of their molecules were considered. The methodology for determining the content of lipophilic xenobiotics by chromatographic methods with mass-selective detection in surface water samples includes a step of separating suspended particles, the content of which in the samples under study was controlled by gravimetric analysis and varied within 135-1500 mg/m3. The target compounds were extracted using n-hexane and acetonitrile. The analytes in the acetonitrile concentrate were determined according to high-performance liquid and gas chromatography with mass-selective detectors (HPLC/MS/MS and GC/MS). The achieved limit of detection of xenobiotics was 0.02 µg/m3, the limit of quantification of xenobiotics was 0.10 µg/m3. To substantiate the possibility of applying the proposed methodology, the following indicators were investigated: linearity of analytical signals with the amount of analytes in the solution, correctness, convergence, and accuracy of measurement results. The linear concentration range of the method for the determination of xenobiotics of diverse groups is 0.10-1.00 µg/m3, characterised by a regression coefficient of the linear dependence of the measurement of individual compounds (R2) exceeding 0.99. The degree of analytes recovery (percentage of recovery r, %) was within 85-120%, which indicates the acceptability of the proposed xenobiotic extraction procedure. The error of the measurement results was calculated as the standard deviation (Sr, %), which did not exceed 6%. The findings of this study suggested that the developed methodology is suitable for monitoring the residual content of active ingredients of agrochemicals in surface waters and predicting the level of water pollution