Sci. Pharm., Volume 90, Issue 3 (September 2022) – 18 articles

It was determined that the studied 5-[(Z)-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone (Les-6222) affects the cyclooxygenase pathway of the arachidonic acid cascade, the markers of damage to neurons on models of PTZ kindling. In the model of chronic epileptogenesis in mice (pentylenetetrazole kindling), a 4-thiazolidinone derivative showed high anticonvulsant activity, which is weaker than the effect of sodium valproate and higher than Celecoxib. The mentioned compound has a pronounced anti-inflammatory effect in the brain on the background of the PTZ kindling, reliably inhibiting COX-1 and COX-2. The predominant inhibition of COX-2 by 44.5% indicates this enzyme’s high selectivity of Les-6222. According to the molecular docking study results, the studied compound revealed the properties of COX-1/COX-2 inhibitor and especially 5-LOX/FLAP. The decreasing content of 8-isoprostane in the brain of mice of the Les-6222 group indicates a beneficial effect on cell membranes in the background of oxidative stress during the long-term administration of PTZ. In addition, Les-6222 significantly decreased the content of neuron-specific enolase, indicating neuroprotective properties in the background of chronic epileptogenesis. The obtained results experimentally substantiate the feasibility of further developing Les-6222 as a promising anticonvulsant agent. Full article

Globally, obesity is a serious health concern that causes numerous diseases, including type 2 diabetes, hypertension, cardiovascular diseases, etc. Medicinal plants have been used to aid in weight loss since ancient times. Thus, this research is focused on the exploration of pancreatic lipase inhibitory activity and secondary metabolite profiling of Bergenia ciliata, Mimosa pudica, and Phyllanthus emblica, selected based on an ethnobotanical survey. The lipase inhibition was investigated using 4-nitrophenyl butyrate (p-NPB) as a substrate. To uncover further therapeutic potentials of these medicinal plants, antimicrobial activity and minimum inhibitory concentration (MIC) of the extracts were also determined. The ethyl acetate plant extracts showed higher antimicrobial activity against Staphylococcus aureus, Escherichia coli, Salmonella typhi, and Shigella sonnei. The MIC of ethyl acetate extracts of medicinal plants considered in this study ranges from 1.56 to 6.25 mg/mL. The hexane fraction of Mimosa pudica and Phyllanthus emblica showed a higher lipase inhibitory activity as compared to others, with IC₅₀ values of 0.49 ± 0.02 and 2.45 ± 0.003 mg/mL, respectively. In the case of Bergenia ciliata, the methanolic extract inhibited lipase more effectively than others, with an IC₅₀ value of 1.55 ± 0.02 mg/mL (IC₅₀ value of orlistat was 179.70 ± 3.60 µg/mL). A mass spectrometry analysis of various solvent/solvent partition fractions (extracts) revealed 29 major secondary metabolites. The research offers a multitude of evidence for using medicinal plants as antiobesity and antimicrobial agents. Full article

The most challenging step in developing bioanalytical methods is finding the best sample preparation method. The matrix interference effect of biological sample become a reason of that. Molecularly imprinted SERS become a potential analytical method to be developed to answer this challenge. In this article, we review recent progress in MIP SERS application particularly in bioanalysis. Begin with the explanation about molecular imprinting technique and component, SERS principle, the combination of MIP SERS, and follow by various application of MIP SERS for analysis. Finally, the conclusion and future perspective were also discussed. Full article

One of the most prevalent over-the-counter cold and cough medications is the chlorpheniramine maleate (CPM)–ibuprofen (IBF) combination. A reversed-phase high-performance liquid chromatography (RP-HPLC) method was effectively optimized and developed for the simultaneous detection of chlorpheniramine maleate and ibuprofen in a pharmaceutical formulation. The mobile phase for the RP-HPLC method was an isocratic combination of acetonitrile and 0.01 M acetate buffer at pH 3.8 (55:45; v/v) on an Eclipse Plus C18 reversed phase column. An ultraviolet (UV) detector with a wavelength of 225 nm was used to detect the analytes at a flow rate of 1.0 mL/min. CPM and IBF were satisfactorily eluted, with mean retention times of 2.09 and 6.27 min, respectively. The approach was shown to be linear (R² > 0.9998 for CPM and 0.9992 for IBF), precise (% RSD 3.02% for CPM and 3.48% for IBF), accurate (% recoveries 97.7–98.9% for CPM and 101–104.5% for IBF), specific, easy to use, sensitive, quick, and robust. Limits of detection (LODs) were found to be 10 and 27 μg/mL for CPM and IBF, respectively. Without interference from excipients, the validated method could be utilized in regular quality control analysis of various dosage combinations of hard gelatin capsules containing CPM and IBF. Full article

The present work includes the synthesis of a new series of quinazolin-4(3H)-one compounds (4a–f, 5a–d) as antimicrobial agents. The starting compound, 2-hydrazinylquinazolin-4(3H)-one (2), was synthesized and treated with different carbonyl compounds to afford the hydrazone derivatives 4a–f. In addition, the hydrazone derivatives 4a–d were treated with a DMF/POCl₃ mixture to give the formyl-pyrazole derivatives 5a–d. All the target compounds were evaluated as antimicrobial agents against four bacterial and four fungal strains. The majority of the tested compounds showed potent antimicrobial activity compared with the reference antibiotics. The most potent antimicrobial activity was shown by 5a with MIC values in the range (1–16) μg/mL. In addition, the most potent compounds against E. coli were evaluated for their inhibitory activity against E. coli DNA gyrase, whereas the target compounds 4a, 5a, 5c, and 5d showed the most potent inhibition to the target enzyme with IC₅₀ values ranging from 3.19 to 4.17 µM. Furthermore, molecular docking studies were performed for the most active compounds against the target E. coli DNA gyrase to determine their binding affinity within the enzyme’s active site. Moreover, ADME evaluations of these compounds predicted their high oral bioavailability and good GI absorption. Full article

A successful candidate for oral drug delivery needs to possess adequate solubility and dissolution rate to elicit its therapeutic action. Extensive research is being carried out to enhance the solubility of poorly soluble drugs through a number of techniques involving polymeric and non-polymeric approaches. Non-polymeric approaches such as micronization and nanocrystals are successful in improving the apparent solubility of drugs, but the sustenance of solubility is not always possible. Amorphous solid dispersions (ASDs) lead to solubility enhancement as well as the maintenance of solubility with the assistance of polymers, thereby improving bioavailability. Spray drying, hot melt extrusion (HME), and KinetiSol^® technologies are some of the techniques capable of manufacturing ASDs. Each of these techniques has its own advantages and disadvantages in terms of processing challenges and applicability in preparing ASDs. The latter two technologies are similar in being fusion and non-solvent techniques to improve solubility. This review compares both HME and KinetiSol^® techniques regarding mechanism, equipment design, formulation, and process parameters involved and scalability. Full article

The search for potential effective antidepressants with minimal side effects is necessary. Peptides are possible applicants for this role. We investigated the antidepressant effect of neuropeptide Y (NY), alone and in combination with clomipramine, in models of acute and chronic stress induced by ultrasound of variable frequencies. Rats were divided into the following groups: the control group, stress group, and stress groups with intranasal administration of NY (100 μg/kg) or clomipramine (7.5 mg/kg), or their combination. Rat behavior was evaluated using a sucrose preference test and forced swimming test in an acute stress model, and a sucrose preference test, forced swimming test, social interaction test, open field test, and Morris water maze test in a chronic stress model. The results of our experiment demonstrated a protective effect of intranasal NY in a model of acute stress, which was comparable to the antidepressant effect of clomipramine. When the same dose was chronically administered, NY also demonstrated an antidepressant action, although expressed in a lesser degree than clomipramine. The combination of NY and clomipramine was much less effective in the chronic stress paradigm compared to the separated drug administration, but was just as effective in the acute stress paradigm. Until now, there was no convincing evidence for the efficacy of the chronic administration of neuropeptide Y; we demonstrated its effectiveness in the animal model of depressive-like behavior. However, our hypothesis that neuropeptide Y can enhance the effect of a classical antidepressant was not confirmed. Full article

The pharmacological effects of medicinal plants play a primary role in the mild correction of body weight in humans and animals, reducing the accumulation of fat in their bodies during a state of obesity. Origanum vulgare L. and Scutellaria baicalensis Georgi are widely used as food additives and medicinal plants, but their comprehensive physiological evaluation in model animals in a state of obesity has not been carried out. In a 30-day laboratory experiment on male rats which had developed obesity through a hypercaloric diet, the effects of adding the dry crushed grass O. vulgare or dry crushed roots of S. baicalensis to their feed was evaluated. During the experiment, the rats fed with O. vulgare increased in body weight to only 105.5% of their initial weight, while the body weight of the control group increased to 111.5%, and that of animals fed on S. baicalensis increased to 124.0% of their initial body weight. The average daily increase in the rats’ body weight when O. vulgare was added to their diet decreased to 205 mg/day, and when S. baicalensis was added, on the contrary, it increased to 1417 mg/day, compared to 700 mg/day among the control group. Under the influence of O. vulgare, the lipid metabolism of the rats normalized: the atherogenic index decreased to 33.7%, compared with the values of the control group, due to an increase in the concentration of high-density lipoproteins from cholesterol. The concentration of triglycerides decreased, and the concentration of glucose decreased. The roots of S. baicalensis being added into the diet of rats increased the activity of alkaline phosphatase and decreased the concentration of urea. The atherogenic index also decreased (by up to 35.5% in the control group) and the concentration of high-density lipoprotein cholesterol increased, while the concentrations of triglycerides and glucose decreased. The physical activity of the rats showed a slight tendency to decrease when both O. vulgare and S. baicalensis were added to their diet. Both plant species contributed to a decrease in the emotional status of animals, which was most pronounced when the O. vulgare grass was added to the feed. The results of the study demonstrate the potential of the use of O. vulgare and S. baicalensis as herbal supplementations for the correction of hyperlipidemia and type-2 diabetes mellitus in overweight patients. Full article

The search for novel photoprotective substances has become a challenge in cosmeceutical research. Streptomyces-derived compounds can serve as a promising source of photoprotective agents to formulate skin photoprotection products, such as sunscreens. This study aimed to identify specialized metabolites with the potential to modulate UV-induced cellular damage in the skin by identifying potential multi-target-directed ligands. Using a combination of ligand- and target-based virtual screening approaches, a public compound library comprising 6524 Streptomyces-derived specialized metabolites was studied for their photoprotective capability. The compounds were initially filtered by safety features and then examined for their ability to interact with key targets in the photodamage pathway by molecular docking. A set of 50 commercially available UV filters was used as the benchmark. The protein–ligand stability of selected Streptomyces-derived compounds was also studied by molecular dynamics (MD) simulations. From the compound library, 1981 compounds were found to meet the safety criteria for topically applied products, such as low skin permeability and low or non-toxicity-alerting substructures. A total of 34 compounds had promising binding scores against crucial targets involved in UV-induced photodamage, such as serotonin-receptor subtype 5-HT_2A, platelet-activating factor receptor_, IL-1 receptor type 1, epidermal growth factor receptor, and cyclooxygenase-2. Among these compounds, aspergilazine A and phaeochromycin F showed the highest ranked interactions with four of the five targets and triggered complex stabilization over time. Additionally, the predicted UV-absorbing profiles also suggest a UV-filtering effect. Streptomyces is an encouraging biological source of compounds for developing topical products. After in silico protein–ligand interactions, binding mode and stabilization of aspergilazine A and phaeochromycin F led to the discovery of potential candidates as photodamage multi-target inhibitors. Therefore, they can be further explored for the formulation of skin photoprotection products. Full article

A series of scalarane sesterterpenes were prepared using heteronemin (1) as a primary precursor. Combined with the scalarane derivatives obtained from natural sources, a total of 22 antitubercular scalaranes were used to build QSAR models based in the 2D-QSAR and CoMFA approaches. Both models indicated the influences of substitutions in the vicinity of C-12 and C-16 of the scalaranes. A 2D-QSAR model suggested the necessity of hydrophilic functionalities on the peripherals with hydrophobic cores, and the lowering steric repulsion to improve the potential energy. This was complemented by the pictorial CoMFA model, which indicated the importance of the positive electrostatic with shortened steric extension crowning over C-12 and the lengthy negative functionalities extended from C-16. Full article

Estrogen receptors (ER) are nuclear hormone receptors which are responsible for sex hormone signaling in women. A series of (1,4-disubstituted)-1,2,3-triazoles 5–21 were prepared by reaction of azidophenols with terminal alkynes under Fokin reaction conditions. The products were purified by column chromatography or recrystallization and characterized by NMR and HRMS. The compounds were tested for binding to ERβ via a ligand displacement assay, and 1-(4-hydroxyphenyl)-α-phenyl-1,2,3-triazole-4-ethanol (21) was found to be the most potent analog (EC₅₀ = 1.59 μM). Molecular docking of 5–21 within the ligand binding pocket of ERβ (pdb 2jj3) was performed and the docking scores exhibited a general qualitative trend consistent with the measured EC₅₀ values. Full article

Colocasia esculenta var. Aquatilis Hassk, elephant ear (CF-EE) has been widely used as traditional food and medicine. It also shows other therapeutic properties, such as antimicrobial and anti-cancer activity. In this study, we aim to investigate the effect of CF-EE extract on apoptosis induction associated with ER stress in cervical cancer HeLa cells. Cell viability was determined by MTT assay. Assessments of nuclear morphological changes, mitochondrial membrane potential, and intracellular reactive oxygen species (ROS) production were conducted by hoeshst33342, JC-1, and DCFH-DA fluorescence staining, respectively. Sub-G1 DNA content was analyzed by flow cytometry, and protein expression was determined by Western blotting. The results demonstrate that CF-EE extract suppressed HeLa cell growth and induced nuclear condensation and apoptotic bodies. There was also a loss of mitochondrial membrane potential and increased apoptosis marker protein expression, including Bax, cleaved-caspase-7, and cleaved-PARP. In addition, the results show that CF-EE extract induced ROS, increased ER stress proteins (GRP78 and CHOP), enhanced p38 and c-Jun phosphorylation, and inhibited Akt expression in HeLa cells. In summary, CF-EE extract induced apoptotic cell death-associated ROS-induced ER stress and the MAPK/AKT signaling pathway. Therefore, CF-EE extract has anticancer therapeutic potential for cervical cancer treatment in the future. Full article

Ruellia tuberosa L. has been previously shown to possess antioxidant and antiproliferative activities on cancer cells but its underlying mechanisms are largely unknown. This study aimed to elucidate the mode of action underlying this inhibitory effect on MCF-7 using ethyl acetate extract obtained after liquid-liquid partition of methanol crude extract. Antiproliferative effect of R. tuberosa ethyl acetate leaf extract (RTEAL) was evaluated using MTT assay. Its ability to induce apoptosis was assessed by DNA ladder formation, JC-1, Annexin V, and methylene blue staining assays. Perturbation of cell cycle progression was determined using flow cytometry. RTEAL was found to selectively inhibit the proliferation of MCF-7 cells with the IC₅₀ value of 28 µg/mL. Morphological changes such as nuclear fragmentation and chromatin condensation were observed although DNA laddering was undetected in agarose gel. RTEAL-induced apoptotic pathways by inhibiting the expression of anti-apoptotic BCL-2 while upregulating pro-apoptotic BAX, caspase 7 and caspase 8. RTEAL also caused cell cycle arrests at the S and G2/M phase and dysregulation of cell cycle regulators. These findings collectively demonstrate that RTEAL extract inhibited cell growth by inducing apoptosis and cell cycle arrest, suggesting its therapeutic potential against breast cancer. Full article

Clonazepam (CLZ), an antipsychotic drug reported for its efficiency in managing anxiety-related disorders, is being marketed only as conventional tablets. Some patients have abstention to swallow the conventional tablets; therefore, the proposed study was aimed at developing a buccal lozenge tablet by direct compression of two types of optimized granules. Conazepam’s water solubility was first enhanced by a solid dispersion technique for a fast and better dissolution of type 1 granules, while the impact of gelling polymers was investigated on controlled-release type 2 granules. The optimized formulae met the acceptable pharmacopeial limits for tablets’ evaluation. A differential scanning calorimetry study revealed the compatibility between the drug and used excipients. All formulae gave a burst release of CLZ in the first hour of investigation, followed by a sustained release over 24 h. The formula that showed the highest prolonged in vitro release (99.0 + 0.1%), following the Higuchi diffusion model (R² = 0.99), was then selected for further study. The formula succeeded in controlling the induced stress in a rat model with a significant impact on the behavioral tests throughout the experiment. The results were further confirmed by a pharmacokinetic study that showed a significant increase in Cmax, Tmax, and AUC (1.5, 2, and 3.9 folds), respectively, compared to oral suspension. The newly proposed delivery system has proven a better efficacy with a reduced dosing frequency. Full article

Sitagliptin (STG) is a highly selective dipeptidyl peptidase-4 inhibitor recently used in the treatment of type 2 diabetes. The current study aimed to investigate the anti-neoplastic effect of STG alone and in combination with Doxorubicin (Dox), a known chemotherapeutic agent but with ominous side effects. After intramuscular inoculation of 2 × 10⁶ Ehrlich tumor cells, Female Swiss mice were divided into tumor-bearing control, STG-treated, Dox-treated, and a combination of STG and Dox-treated groups. The results showed a significant reduction in the tumor growth of the treated animals in comparison with those of the positive control group with a more prominent effect in the co-treated group. Where, the anti-proliferative and apoptotic effect of STG, and its chemo-sensitizing ability, when used in combination with Dox, was mediated by modulation of oxidative stress (MDA and GSH), attenuation of tumor inflammation (IL-6 and IL-1β), and angiogenesis (VEGF), suppressing proliferation (β-catenin and cyclin-D1) and enhancement of apoptosis (survivin, p53, caspase 3). Thus, in conclusion, STG as adjunctive therapy for Dox could be a strategy for the treatment of breast cancer patients, by their ability in hindering cell proliferation and minimizing the associated oxidative and inflammatory adverse reactions. Full article

Wound healing comprises organized events involving tissue repair and regeneration. The discovery of toll-like receptors (TLRs) sheds recent light on the mechanisms involved in initiating inflammatory responses throughout the healing cascades. Hibiscus sabdariffa (HS) components may exhibit a wound healing action, owing to their antioxidant and anti-inflammatory activities. This study was designed to investigate the early effects of HS loaded in an ointment base on wound healing, antioxidant, antimicrobial effects, burning intensity, and histopathological features on the rat burn model in comparison to the standard treatment, Iruxol^® ointment. A burn injury model was used to evaluate the wound healing potency of the preparation. Rats were treated with ointments three times on the day of the induction of the burn. Findings revealed that the strong antioxidant properties of the HS-loaded ointment augmented the skin healing potential by stimulating biomarkers required for skin regeneration. HS repressed the burning-induced inflammation by the effective reduction in the levels of tumor necrosis factor α (TNF-α) and IL-6 through TLR4 protein inhibition. Topical HS downregulates transforming growth factor-beta (TGF-β) levels. HS extract possesses a potential bactericidal activity against highly resistant clinical isolates of Pseudomonas aeruginosa. Overall, this study proclaims that HS-loaded topical preparations could be a valuable product that serves as adjuvants to accelerate burn wound healing through inactivating the TLR4 pathway. Full article

Conventional chemotherapy for colorectal cancer (CRC) gives only a small increase in patient survival, since it is often diagnosed at late stages, when the tumor has disseminated to other organs. Moreover, it is common to observe that malignant cells may acquire resistance to conventional chemotherapies through different mechanisms, including reducing drug activation or accumulation (by enhancing efflux), inducing alterations in molecular targets, and inhibiting the DNA damage response, among other strategies. Considering these facts, the discovery of new molecules with therapeutic potential has become an invaluable tool in chemoprevention. In this context, we previously evaluated two hybrids (SAC-CAFA-MET and SAC-CAFA-PENT) that exhibited selective cytotoxicity against SW480 cells, with better results than the conventional chemotherapeutic agent (5-fluorouracil; 5-FU). Here, we investigated the possible mechanisms of these molecules in greater depth, to identify whether they could be valuable therapeutic scaffolds in the search for new molecules with chemopreventive potential for the treatment of CRC. Both compounds reduced ROS formation, which could be related to antioxidant effects. Further evaluations showed that SAC-CAFA-MET induces cell death independent of caspases and the tumor-suppressor protein p53, but probably mediated by the negative regulation of the pro-apoptotic Bcl-2. In addition, the lack of activation of caspase-8 and the positive regulation of caspase-3 induced by SAC-CAFA-PENT suggest that this compound acts through an apoptotic mechanism, probably initiated by intrinsic pathways. Furthermore, the downregulation of IL-6 by SAC-CAFA-PENT suggests that it also induces a significant anti-inflammatory process. In addition, docking studies would suggest caspase-3 modulation as the primary mechanism by which SAC-CAFA-PENT elicits apoptosis in SW480human colorectal adenocarcinoma cells. Meanwhile, density functional theory (DFT) calculations suggest that both hybrids would produce effects in the modulation of ROS in SW480 cells via the hydrogen atom transfer (HAT) pathway. The present work notes that SAC-CAFA-MET and SAC-CAFA-PENT could be potential candidates for further investigations in the search for potential chemopreventive agents. Full article

Burn injuries can have a lasting effect on people’s quality of life, as they negatively impact their physical and mental health. Then, they are likely to suffer psychological problems as a result. A serious problem is that deep burns are more challenging to treat due to their slow healing rate and susceptibility to microbial infection. Conventional topical medications used for burn treatment are sometimes ineffective because they cannot optimize their ability of transcutaneous absorption at the targeted site and accelerate healing. However, nanotechnology offers excellent prospects for developing current medical wound therapies and is capable of addressing issues such as low drug stability, water solubility, permeability, and bioavailability. The current review focuses on lipid-based vesicles (vesiculosomes) as an example of advanced delivery systems, showing their potential clinical applications in burn wound management. Vesiculosomes may help overcome impediments including the low bioavailability of active agents, offering the controlled release of drugs, increased drug stability, fewer side effects, and reduced dosing frequency, which will ultimately improve therapeutic efficacy and patient compliance. We discuss the application of various types of vesiculosomes such as liposomes, niosomes, ethosomes, cubosomes, transfersomes, and phytosomes in burn healing therapy, as these demonstrate superior skin penetration compared to conventional burn topical treatment. We also highlight their noteworthy uses in the formulation of natural products and discuss the current status as well as future perspectives of these carriers in burn management. Furthermore, the burn treatment options currently available in the market are also summarized. Full article