ScienceRise: Pharmaceutical Science

Computer-aided rational design and synthesis of new potential antihypertensive agents among 1,2,3-triazole-containing nifedipine analogs

Sun, 30 Jun 2024 00:00:00 +0300

1,2,3-Triazole-containing Nifedipine analogues offer the opportunity to increase biostability, bioavailability, efficacy and binding selectivity to target receptors. Here, we applied a computer-aided rational design for identifying new Nifedipine analogues containing a 1,2,3-triazole moiety. First, a new chemical library of 796 derivatives combining the DHP fragment and 1,2,3-triazole moiety was generated. Second, to reduce the library size, the library was pre-filtered using two 3D-pharmacophore models with different complexity, which allowed us to gradually reduce the chemical space, ending up with 26 hit candidates. Molecular docking calculations against the rCav1.1 receptor allowed the identification of eight derivatives 5a-h, characterized by the binding affinity towards the rCav1.1 receptor of the same level as approved Nifedipine-like drugs. Next, our molecular docking results were used to guide and optimize the retrosynthetic approaches for new analogues of Nifedipine as promising antihypertensive agents. So, a retrosynthetic approach for Nifedipine analogues with a 1,2,3-triazole ring in position 4 was proposed. Finally, eight analogues 5a-h determined by molecular docking calculations were synthesized using the suggested retrosynthetic approach.

The aim of this study is to identify new Nifedipine analogues using a computer-aided drug design and a retrosynthetic approach.

Materials and Methods. The organic synthesis of new Nifedipine analogues containing a 1,2,3-triazole moiety. Computer-aided drug design of new DHP derivatives using pharmacophore screening and molecular docking calculations.

Results. Molecular docking of new Nifedipine analogues made it possible to estimate the binding affinity of new Nifedipine derivatives to the rCav1.1 receptor. Pharmacophore screening of a chemical library of analogues, consisting of 796 derivatives, allowed gradually reducing the chemical space and obtaining 26 candidates with high affinity to the rCav1.1 receptor. Using the method of molecular docking, eight hits 5a-h were identified, and the synthesis of the recommended compounds was proposed and performed.

Conclusions. The results of molecular docking showed that Nifedipine analogues are characterized by binding affinity to the rCav1.1 receptor at the same level as approved Nifedipine-like drugs. Pharmacophore screening and molecular docking calculations indicate key features of the ligand-receptor interaction that can guide and optimize the synthesis of new Nifedipine analogues as promising new antihypertensive agents. A retrosynthetic approach was proposed, and the recommended compounds were synthesized

Study of the effect of ethanol on the properties of poloxamer 338 solutions by rotational viscometry and spin probe method

Oleksii Liapunov, Elena Bezuglaya, Anna Liapunova, Oleksii Lysokobylka — Sun, 30 Jun 2024 00:00:00 +0300

The aim. Study the properties of 20 % solutions of poloxamer 338 (P338) in water and mixed solvents water-ethanol using rotational viscometry and the spin probe method at various temperatures.

Materials and methods. 20 % m/m solutions of P338 in water and water – ethanol mixtures were the objects of research. The solutions were studied by rotational viscometry at various temperatures; the flow behaviour, lower yield stress (t₀) and dynamic or apparent viscosity (η) were determined. Spin probes based on fatty acids, which differ in molecular structure, solubility, and radical localization, were added to the solutions. Electron paramagnetic resonance (EPR) spectra were obtained to determine their type and parameters.

Results. Depending on the content, ethanol affects the rheological properties of 20 % solution of P338. The solution was demonstrated to be able to thermally induce sol → gel transition at 32 °C when ethanol content is 5 % m/m. The rheological parameters of the gel at 32 °C and 37 °C exhibit an increase (in comparison to the gel without ethanol), accompanied by a reduction in the packing density of polypropylene oxide (PPO) chains within the cores of P338 micelles. At an ethanol content of 10 % m/m, the gel formation temperature rises to 40 °C. At ethanol content of 15 % m/m and above, 20 % P338 solutions do not form gels at temperatures between 25 °C and 40 °C. The values of rotational correlation times (τ) and the order parameter (S) of fatty acid-based spin probes were observed to decrease with increasing ethanol content up to 30 % m/m; in the case of the ammonium salt of 5‑doxylstearic acid (5-DSA NH4 salt), the anisotropic EPR spectra transform, becoming a superposition of two triplets and subsequently a triplet. P338 solutions retain their ability to undergo thermally induced sol ↔ gel transitions as long as the EPR spectra of this probe exhibit anisotropy at temperatures ranging from 25 °C to 37 °C. As the concentration of ethanol in the solution increases, the solvation of the cores of P338 micelles by the dispersion medium of the solution also increases.

Conclusions. It was demonstrated that ethanol, when added to the 20 % P338 solution, results in changes to the rheological properties of this solution. However, at the ethanol content of 5-10 % m/m, the ability of P338 to thermally induce sol → gel transition remains unaltered. The rheological properties of the 20 % P338 solution exhibit a correlation with the observed change in EPR spectra types for the 5-DSA NH₄ salt. As the ethanol content in the solution increases, the solvation of P338 micelle cores by the dispersion medium increases, accompanied by decreased density and orderliness of the PPO chains packing in the micelle cores

Pharmacological and technological studies in the development of tablet composition with acorus calamus leaf extract

Sun, 30 Jun 2024 00:00:00 +0300

The aim: To determine the optimal qualitative and quantitative composition of auxiliary substances for tablets containing dry extract of Acorus calamus leaves and the solid dispersion of quercetin, their relatively therapeutic dose and antiexudative activity.

Materials and methods: This study determined a relatively therapeutic dose of dry extract of Acorus calamus leaves, investigated the impact of various auxiliary substances on the properties of tablets formulated with active ingredients - dry extract of Acorus calamus leaves and solid dispersion of quercetin, and assessed antiexudative activity these tablets. The comprehensive analysis entailed the utilization of standardized pharmacopoeial methods to evaluate the quality of the tablet samples. These methods encompassed a range of assessments designed to ensure that the tablets met the requisite pharmacological standards, focusing on key characteristics such as dissolution rate and stability. Determination of the relatively therapeutic dose and antiexudative activity made using standard pharmacological methods in laboratory rats.

Results: In-depth exploration during the study led to identifying Ac-Di-Sol and Lubripharm SSF as the most suitable auxiliary substances for the tablet composition. Detailed analysis revealed that Ac-Di-Sol, when utilized at a 10 % concentration, markedly improved the tablets' disintegration rate without adversely affecting their structural integrity. Concurrently, Lubripharm SSF was observed to significantly enhance the tablets' mechanical stability by reducing their friability.

Conclusions: As a result of the study, the relatively therapeutic dose of dry extract of Acorus calamus leaves, and the solid dispersion of quercetin, optimal auxiliary substances for the tablet formulation - Ac-Di-Sol and Lubripharm SSF - were established. The conducted research enabled the development of a tablet composition that aligns with the requisite pharmacotechnological specifications and conditions of the modern pharmaceutical industry and demonstrates high antiexudative activity relative to monocomponent substances and famous drugs

A qualitative and quantitative analysis of polyphenolic compounds in five Epilobium spp. with a possible potential to alleviate benign prostatic hyperplasia

Sun, 30 Jun 2024 00:00:00 +0300

Benign prostatic hyperplasia (BPH) is a widespread male disease, affecting more than 50 % of men over the age of 60 years. Inhibition of the enzyme 5α-reductase is a common treatment strategy for this condition. Such potential can be found in willow flowers (Epilobium spp.), which are known in folk medicine for treating of prostate ailments, mainly benign prostatitis, hypertrophy and prostatitis. Smallflower hairy willowherb (E. parviflorum), which is rare, is the most recommended for treating BPH.

The aim. The aim of the study was to investigate the qualitative and quantitative content of polyphenols in five Epilobium species (E. adenocaulon Hausskn., E. hirsutum L., E. montanum L., E. parviflorum Schreb. and E. palustre L.) growing in Estonia, to find the most promising species in terms of chemical composition to alleviate BPH.

Materials and Methods. The qualitative and quantitative analyses of polyphenols in herbs of Epilobium spp. were performed using HPLC/MS. All five species were collected from the pond's shore in Pilkuse village (Otepää municipality, Valga county, Estonia) in July 2008.

Research results. It was found that 20 % ethanol was optimal for extracting polyphenolic compounds from the herb Epilobium spp. with subsequent UV chromatogram analysis at 350 nm. In the analyzed Epilobium species, 12 polyphenolic compounds were identified. Oenothein B, myricetin rhamnoside and myricetin glucoside were the principal polyphenolic compounds among other identified constituents in the Epilobium spp. herbs. E. montanum had the highest content of oenothein B. The highest was the total content of myricetin glycosides for all five compared species, the total content of quercetin glycosides was slightly lower, and the total content of kaempferol glycosides was the lowest.

Conclusions. The content of polyphenols is highest in E. adenocaulon and the lowest in E. parviflorum. Thus, E. parviflorum does not offer the best therapeutic potential for the to relief of BPH in terms of the quantitative content of polyphenolic compounds

Novel eco-friendly spectrophotometric determination of lercanidipine hydrochloride in tablets using methyl red

Sun, 30 Jun 2024 00:00:00 +0300

The aim of the work was to develop a simple, eco-friendly, quick, affordable and alternative spectrophotometric procedure that uses the azodye methyl red (MR) for the determination of lercanidipine in its dosage form considering the “green” chemistry principles.

Materials and methods. Analytical equipment: Shimadzu UV-1800 double beam UV-visible spectrophotometer (Japan) with included UV-Probe 2.70 software, RAD WAG AS 200/C precise analytical balance (Poland), Elmasonic EASY 40H ultrasonic bath.

Lercanidipine hydrochloride (purity 99 %) was purchased from Jiyan Chemicals (India). Lercanidipine tablets 10 mg and 20 mg were used in our experiments.

Results and discussion. To determine the amount of lercanidipine in tablets, a spectrophotometric method has been developed. To select the best dye for the method development, we tested a variety of dyes, including MR, bromocresol purple, bromophenol blue, cresol red, bromocresol green and bromothymol blue. We selected MR as the reagent based on the experimental studies' outcomes, and the solvent was an acetonitrile and ethanol mixture with a ratio of 95 to 5. The optimal parameters were determined for the quantitation of lercanidipine in tablets utilizing MR with 5×10^-5 mol/L of dye concentration, 0.5 ml of MR solution, at a temperature of 25 °C without heating; detection wavelength was 498 nm and reaction time of 5 min. By using the molar ratios (saturation) method and Job's (continuous variations) approach, the stoichiometric coefficients of reacting components involving lercanidipine and dye were established to be 1:1. The proposed spectrophotometric procedure was linear within the concentration ranging from 6.48 – 32.41 μg/mL. Using the least squares method, a regression equation was generated: y = 0.0208x – 0.0318. The correlation coefficient was higher than 0.999, indicating that the analytical procedures' linearity is acceptable; the limit of detection and limit of quantitation were 1.19 μg/mL and 3.62 μg/mL, respectively. The robustness, accuracy and precision of the study results fell within acceptable limits. The proposed method was successfully applied to determine the content of lercanidipine in its tablet dosage forms. The analysis of the method's "greenness" using AGREE and GAPI tools yielded excellent results.

Conclusions. The method that has been developed can serve as an alternative approach for the routine control of lercanidipine content in its tablets

Comparative pharmacognostic study of the roots of the most common species of plants of the genus arctium

Sun, 30 Jun 2024 00:00:00 +0300

The aim is to carry out a comparative pharmacognostic study of the roots of A. tomentosum and A. minus with the root of A. lappa to confirm or deny their interchangeability.

Materials and methods. A Delta optic BioLight 300 microscope (Poland) was used to study the macro- and microscopic features of plant raw materials. The method of gas chromatography-mass spectrometry was used to identify and quantify organic, including fatty, acids. Quantitative content of amount of organic acids, ascorbic acid, total polyphenols and amount of hydroxycinnamic acids was determined by using spectrophotometry. The content of polysaccharides was determined by the gravimetric method.

The results. For the first time, a comparative morphological and anatomical study of the roots of A. tomentosum and A. minus in comparison with the root of A. lappa was carried out. As a result, a distinctive diagnostic microscopic feature of the roots was established: the shape of the receptacles of the schizogen type. For the first time, the component composition of organic, including fatty acids, for the roots of A. tomentosum and A. minus was determined in comparison with the root of A. lappa, which is the same. The content of 11 organics and 12 fatty acids in plant raw materials of 3 Arctium species was identified and determined. The quantitative content of the amount of organic acids, ascorbic acid, polysaccharides, total polyphenols, and amount of hydroxycinnamic acids in the roots of A. tomentosum and A. minus in comparison with the root of A. Lappa was established, and these indicators are comparable.

Conclusions. For the first time, a comparative pharmacognostical study of the roots of A. tomentosum and A. minus in comparison with the root of A. lappa was carried out which showed minor differences between the roots of these Arctium species and confirms their interchangeability at this stage, especially when harvesting wild plant raw materials, when identification of the species at the botanical level is impossible

Analysis of the essential oils in leaves and rhizomes with roots of angelica Archangelica growing in Ukraine

Sun, 30 Jun 2024 00:00:00 +0300

Essential oils, comprised of volatile compounds, have a wide range of biological effects, making them valuable in medicine, industry, and agriculture. They exhibit properties such as antimicrobial, anti-inflammatory, antiviral, antioxidant, anti-obesity, antidiabetic, and smooth muscle relaxation. In this aspect, plants belonging to the genus Angelica show promise. One of these essential oil plants is Angelica archangelica. There is insufficient information in the literature on the essential oils of the leaves and rhizomes with roots of Angelica archangelica.

The aim. The aim of our study was to identify and determine the quantitative content of essential oils by GC/MS method in Angelica archangelica leaves and rhizomes with roots grown in Ukraine.

Materials and methods. The determination of the essential oils composition of Angelica archangelica was conducted using Agilent Technologies 6890 chromatograph with mass spectrometric detector 5973 (Agilent Technologies, USA).

Results. The leaves of Angelica archangelica were found to contain twenty-three components in their essential oil, while the rhizomes and roots of this plant contained fifteen components. Eleven components were common to both parts of the plant, namely cis-Pinane, α-Farnesene, α-Curcumene, α-Caryophyllene, Copaen, β-Bisabolene, δ-Amorphene, α-Muurolene, trans-Chrysanthemal, β-Guaiene, α-Elemene. Twelve components such as α-Pinene, β-Myrcene, 3-p-Menthene, Isoborneol, Anisole, Bornyl acetate, (Z)-β-Elemene, Caryophyllene, (-)-Spathulenol, α-Bergamotene, γ-Muurolene, α-Bisabolol were present only in leaves, and four components namely p-Isopropenylacetophenone, β-Cubebene, α-Zingiberene, Hexahydrofarnesyl acetone were present only in rhizomes with roots.

Conclusions. The component composition of the essential oil in the leaves and the rhizomes with roots of Angelica archangelica growing in Ukraine was investigated using the GS/MC method. We have defined for the first time the chemical composition of the essential oils of the leaves of Angelica archangelica, 23 components of essential oil were identified. In the rhizomes with roots, 15 components of essential oils were identified. The following pharmacologically important components, cis-Pinane and α-Farnesene, were found in both samples of the essential oil of Angelica archangelica in significant quantities. These results have been cross-analyzed and are particularly important for planning and defining the process of cultivation and use of this species plant in traditional and official medicine

CYP2C19 polymorphisms on escitalopram treatment outcome in South Indian population with major depressive disorder

B Jeevan Kumar, Vijayakumar Thangavel Mahalingam, Ganesh Kumar — Sun, 30 Jun 2024 00:00:00 +0300

Various CYP2C19-mediated metabolizer groups may arise as a result of inter-individual variability, which potentially influences the efficacy and safety of escitalopram. Hence, it is crucial to establish a comprehensive collection of information relevant to each phenotype regarding the efficacy and tolerability of therapy. This will enable psychiatrists to make optimal decisions for individual patients.

The aim of the study: The aim of this study is to classify MDD patients into various CYP2C19 metabolizer groups and to determine the association between phenotype and treatment outcome.

Materials and Methods: The study enrolled 119 escitalopram monotherapy-treated MDD patients aged 18–58. MADRS, HDRS-17, and CGI were used to measure efficacy at baseline, weeks 4, 8, and 12. Safety and tolerability outcomes were examined from occurring ADRs. Clinical outcomes were compared among phenotypes based on changes in HDRS-17 and CGI scores from week 4 to week 12.

Results: Subjects were categorized by CYP2C19 genotype: 20 poor (PM), 64 intermediate (IM), 24 extensive (EM), and 11 ultra-rapid (UM) metabolizers. Response and remission occurred in 67.2 % and 26.8 % of the 119 subjects at the end of the 12th week of the study. The response rate in PM was much lower (21.6 %) compared to EM. There were 312 adverse drug reactions (ADRs), and 88 (73.94 %) individuals had at least one. In safety data, nervousness was the most common ADR among the four groups 66 (55.4 %), followed by decreased appetite 48 (40.3 %). There were no severe ADRs. Men had more ADRs than women.

Conclusion: CYP2C19 genotyping may help personalize escitalopram medication. The study found that the reduced ability of PM to metabolize escitalopram is probably associated with the decreased efficacy and tolerance shown in PM compared to EM and IM. The relationship between metabolizer status and treatment response followed the anticipated direction. Our findings should guide future clinical studies that include pharmacokinetic assessments

Study of the influence of the extract of pipsissewa on cell cultures

Oleksiy Kovregin, Volodymyr Prokopiuk, Dmytro Lytkin, Inna Vladymyrova — Sun, 30 Jun 2024 00:00:00 +0300

The development of new diuretics of plant origin is an actual direction. Chimaphila umbellata (L.) is a perennial herb with diuretic, astringent, analgesic and other effects; and it can treat various conditions such as edema, dropsy, etc. Pipsissewa herb helps the removal of nitrogenous and chloride salts from the body due to the content of arbutin glycoside, tannins (up to 5 %).

The aim. Evaluation of the effect of pipsissewa extract on L929 cell culture.

Materials and methods. Cell line L929 (fibroblasts of mouse adipose tissue) was obtained in the low-temperature bank of the Institute of Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine. Cells were cultured in DMEM medium (Bio West, France) enriched with 10 % FBS (Lonza, Germany) with 1 % antibiotic-antimycotic (Bio West, France), in a CO₂ incubator (Thermo Fisher Scientific, USA) at 37 ºC in an atmosphere with 5 % CO₂.

Determination of the minimum toxic concentration at which the cells remained alive was evaluated by morphological features (shape, monolayer integrity, adhesion to plastic). The study of the effect of pipsissewa extract on various cell functions was determined by the following methods: the ability to preserve morphological integrity - by the phase-contrast microscopy method, energy exchange - by the MTT test method, pinocytotic function - by the neutral red absorption method, migratory function - by the scratch test method, proliferative activity - by the doubling calculation method population

Results. It is proposed to use concentrations of 0.05, 0.02, 0.01, 0.005 % of pipsissewa extract for further research. After carrying out the MTT reaction, the transition of MTT to formazan was confirmed microscopically in the negative control (native cells), at PE concentrations of 0.01 % and below, and the absence of a reaction in the positive control (cells killed by ethanol) at PE concentrations above 0.02 %. When recording the parameters of the NP absorption reaction, it was determined that PE at a concentration of 0.02 % and higher sharply suppresses pinocytotic activity, despite the partial preservation of cell adhesion, reducing the concentration by two times no longer affects mitochondria. A concentration of 0.01 % reduces proliferative activity, and at a concentration of 0.005 %, no difference with the control values was found.

Conclusions. When studying the assessment of the effect of pipsisewa extract on L929 cell culture, a toxic effect on these cells was established when added to the culture medium at a concentration above 0.01 %. The toxic effect had a threshold effect. Migratory and proliferative functions were the most sensitive, energy, pinocytosis and preservation of morphological integrity of cells were less sensitive

Study of the identity of the polymorphic form of API – dapagliflosin derivative and of its permanency structure under the influence of the tableting process

Yevhenii Bohuslavskyi, Halyna Voskoboinikova, Andriy Goy, Svetlana Shishkina — Sun, 30 Jun 2024 00:00:00 +0300

The aim. To investigate the polymorphic structure of the API – Dapagliflozin propanediol monohydrate and to reveal the absence of an effect of the tabletting process on the polymorphic structure of the API in model compositions of tablets.

Materials and methods. Model mixtures of API - dapagliflozin propanediol monohydrate and excipients were studied. The research used the method of designing pharmaco-technological parameters of solid dosage forms, the method of quantum-chemical modelling of the mechanical properties of polymorphic modifications of APIs, the modelling of shear deformation, the nanoindentation method, the Rietveld method for calculating X-ray patterns, X-ray structural analysis of API and selected model compositions of tablets.

Results. The polymorphic structure of API - dapagliflozin propanediol monohydrate and its polymorphic structure in selected model compositions of tablets produced by the pressing method were studied and analyzed. An X-ray structural study was carried out, and the qualitative and phase composition of samples and polymorphic modifications of API and model series of tablets were determined. According to the results of the X-ray structural analysis, it was established that there is no polymorphic transition and that the polymorphic structure of API is invariant under the influence of pressing pressure, which ensures the quality of the tablet form.

Conclusions. The design of an experimental study was determined based on the application of the QbD concept, design of experiments – DoE, for designing and ensuring a high-quality technological process – tabletting of API - Dapagliflozin propanediol monohydrate and excipients.

To manage a critical technological parameter - the stability of the polymorphic structure of the API, which guarantees the quality of the tablet form, its bioavailability and bioequivalence, it is necessary to use a set of methods for studying structural changes and polymorphic modifications of the API during the tableting process.

According to the results of the X-ray structural study of API and selected model compositions of tablets, it was established that during the process of tabletting under pressure, the structure of the polymorphic modification of dapagliflozin propanediol monohydrate does not change, and no polymorphic transition is observed