LC-ESI-MS/MS-Based Comparative Metabolomic Study, Antioxidant and Antidiabetic Activities of Three Lobelia Species: Molecular Modeling and ADMET Study.

The hydroethanol (70%) extracts of three Lobelia species (L. nicotianifolia, L. sessilifolia, and L. chinensis) were analyzed using LC-ESI-MS/MS. Forty-five metabolites were identified, including different flavonoids, coumarin, polyacetylenes, and alkaloids, which were the most abundant class. By applying Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) based on LC-ESI-MS/MS analysis, the three species were completely segregated from each other. In addition, the three Lobelia extracts were tested for their antioxidant activities using a DPPH assay and as antidiabetic agents against α-glycosidase and α-amylase enzymes. L. chinensis extract demonstrated significant antioxidant activity with an IC50 value of 1.111 mg/mL, while L. nicotianifolia showed mild suppressing activity on the α-glycosidase activity with an IC50 value of 270.8 µg/mL. A molecular simulation study was performed on the main compounds to predict their potential antidiabetic activity and pharmacokinetic properties. The molecular docking results confirmed the α-glycosidase inhibitory activity of the tested compounds, as seen in their binding mode to the key amino acid residues at the binding site compared to that of the standard drug acarbose. Furthermore, the predictive ADMET results revealed good pharmacokinetic properties of almost all of the tested compounds. The biological evaluation results demonstrated the promising activity of the tested compounds, aligned with the in silico results.

Eucalyptus Oils Phytochemical Composition in Correlation with Their Newly Explored Anti-SARS-CoV-2 Potential: in Vitro and in Silico Approaches.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the latest arisen contagious respiratory pathogen related to the global outbreak of atypical pneumonia pandemic (COVID-19). The essential oils (EOs) of Eucalyptus camaldulensis, E. ficifolia F. Muell., E. citriodora Hook, E. globulus Labill, E. sideroxylon Cunn. ex Woolls, and E. torquata Luehm. were investigated for its antiviral activity against SARS-CoV-2. The EOs phytochemical composition was determined using GC/MS analysis. Correlation with the explored antiviral activity was also studied using multi-variate data analysis and Pearson's correlation. The antiviral MTT and cytopathic effect inhibition assays revealed very potent and promising anti SARS-CoV-2 potential for E. citriodora EO (IC50 = 0.00019 µg/mL and SI = 26.27). The multivariate analysis revealed α-pinene, α-terpinyl acetate, globulol, γ -terpinene, and pinocarvone were the main biomarkers for E. citriodora oil. Pearson's correlation revealed that globulol is the top positively correlated compound in E. citriodora oil to its newly explored potent anti SARS-CoV-2 potential. A molecular simulation was performed on globulol via docking in the main active sites of both SARS-CoV-2 viral main protease (Mpro) and spike protein (S). In silico predictive ADMET study was also developed to investigate the pharmacokinetic profile and predict globulol toxicity. The obtained in silico, in vitro and Pearson's correlation results were aligned showing promising SARS-CoV-2 inhibitory activity of E. citriodora and globulol. This study is a first record for E. citriodora EO as a novel lead exhibiting potent in vitro, and in silico anti SARS-CoV-2 potential and suggesting its component globulol as a promising candidate for further extensive in silico, in vitro and in vivo anti-COVID studies.

Virtual screening approach for the discovery of selective 5α-reductase type II inhibitors for benign prostatic hyperplasia treatment.

Background: 5α-Reductase type II (5αR2) inhibition is a promising strategy for benign prostatic hyperplasia treatment. A computational approach including virtual screening, ligand-based 3D pharmacophore modeling, 2D quantitative structure-activity relationship and molecular docking simulations were adopted to develop novel inhibitors. Results: Hits were first filtered via the validated pharmacophore and 2D quantitative structure-activity relationship models. Docking on the recently determined cocrystallized structure of 5αR2 showed three promising hits. Visual inspection results were compared with finasteride ligand and dihydrotestosterone as reference, to explain the role of binding to Glu57 and Tyr91 for 5αR2 selective inhibition. Conclusion: Alignment between Hit 2 and finasteride in the binding pocket showed similar binding modes. The biological activity prediction showed antitumor and androgen targeting activity of the new hits.

Natural compounds as possible anti-SARS-CoV-2 therapeutic agents: an in-vitro and in-silico study.

WHO declared severe acute respiratory syndrome coronavirus-2' (SARS-CoV-2) was global health emergency since 2020. In our study eighteen natural compounds were investigated for possible anti-SARS-CoV-2 potential, where the most potent natural compounds were ursolic acid and dioscin with IC50 value of 4.49 µg/mL and 7.11 µg/mL, respectively. Hesperidin, catechin, diosmin, isorhamnetin-3-O-glucoside and hyperoside showed medium antiviral activity with IC50 value of 20.87, 22.57, 38.92, 39.62 and 47.10 µg/mL, respectively. Molecular modelling studies including docking study and predictive ADME study were performed on all tested molecules. Their binding energies after docking were calculated and their orientations at the active sites of both SARS-CoV-2 main protease (Mpro) and spike (S) receptors were visualised and compared to the downloaded ligands. Also, the predictive ADME studies showed good pharmacokinetic properties of most of the tested compounds. The obtained in silico results obtained confirmed that many of the tested compounds are promising SARS-CoV-2 inhibitors.

Team-based learning-adopted strategy in pharmacy education: pharmacology and medicinal chemistry students' perceptions.

Background: Team-based learning (TBL) provides an advanced teaching method for healthcare education; it is characterised by being an interactive teaching session that allows groups of learners to work together in teams to discuss and apply what they have learnt to certain clinical scenarios. The following study aims to evaluate the impact of TBL strategy on the students' comprehension and acquired knowledge, to allow better application and integration of knowledge. The aim of the study was to improve pharmacy students' skills in achieving learning outcomes by adapting TBL pedagogy in the lectures. Students' feedbacks were collected via post-lecture survey. Results: The study was applied to pharmacy students covering two courses: Pharmacology III (Level 4) and Medicinal Chemistry I (Level 3) in a period of two-week lectures through the first semester of the academic year 2021/2022 in Future University in Egypt. The selected topics-related preparation materials were previously available on each course moodle page prior to the actual lecture, for the students to get prepared including growth hormone, sex hormones and their associated diseases for the pharmacology course and COVID-19 management for the Medicinal Chemistry course. The TBL lecture was started by dividing the students into teams and then readiness assurance tests were given, as individual readiness assurance test and then team readiness assurance test conceptual test were applied. The assessment of the students' decision-making skills and problem solving was evaluated through solving-related clinical cases. All the learning outcomes were achieved with maximum participation and interaction via an open discussion between the lecturer and the students during the lecture. A total of 116 students answered the survey and confirmed their satisfaction, better understanding and more participation in TBL lectures compared to other topics taught with the ordinary methods. More than half of the students recommended the TBL method for better perception and participation. Conclusion: The students felt great appreciation for the team-based lecturing. Also, recommendations and suggestions were directed towards increasing the percentage of TBL lectures in the curriculum, as it helped them to concentrate more with high participation levels.

Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity.

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4-15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.

Discovery of pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives as novel CDK2 inhibitors: synthesis, biological and molecular modeling investigations.

CDK2 inhibition is an appealing target for cancer treatment that targets tumor cells in a selective manner. A new set of small molecules featuring the privileged pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffolds (4-13) as well as the thioglycoside derivatives (14, 15) were designed, and synthesized as novel CDK2 targeting compounds. The growth of the three examined cell lines was significantly inhibited by most of the prepared compounds. Results revealed that most of the compounds showed superior cytotoxic activities against MCF-7 and HCT-116 with IC50 range (45-97 nM) and (6-99 nM), respectively, and moderate activity against HepG-2 with IC50 range of (48-90 nM) compared to sorafenib (IC50: 144, 176 and 19 nM, respectively). Of these compounds, 14 & 15 showed the best cytotoxic activities against the three cell lines with IC50 values of 45, 6, and 48 nM and 46, 7, and 48 nM against MCF-7, HCT-116 and HepG-2, respectively. Enzymatic inhibitory activity against CDK2/cyclin A2 was achieved for the most potent anti-proliferative compounds. Compounds 14, 13 and 15 revealed the most significant inhibitory activity with IC50 values of 0.057 ± 0.003, 0.081 ± 0.004 and 0.119 ± 0.007 µM, respectively compared to sorafenib (0.184 ± 0.01 µM). Compound 14 displayed potent dual activity against the examined cell lines and CDK2, and was thus selected for further investigations. It exerted a significance alteration in cell cycle progression, in addition to apoptosis induction within HCT cells. Molecular docking simulation of the designed compounds confirmed the good fit into the CDK2 active site through the essential hydrogen bonding with Leu83. In silico ADMET studies and drug-likeness studies using a Boiled Egg chart showed suitable pharmacokinetic properties which helped in structure requirement prediction for the observed antitumor activity.

Synthesis, Characterization and Host-Guest Complexation of Asplatin: Improved In Vitro Cytotoxicity and Biocompatibility as Compared to Cisplatin.

Para-sulfocalix[n]arenes are promising host molecules that can accommodate various chemotherapeutic drugs. Pt(IV)-based complexes, including satraplatin and asplatin, are promising alternatives that overcome the shortcomings of Pt(II) complexes. In this study, asplatin has been synthesized by fusing acetylsalicylic acid (aspirin) and cisplatin. Furthermore, it has been characterized using 1H NMR, mass spectrometry, elemental analysis, and UHPLC. A host-guest complex of asplatin and p-sulfocalix[4]arene (PSC4) has been developed and characterized using UV, Job's plot analysis, HPLC, and density functional theory (DFT) calculations. The experimental and computational investigations propose that a 1:1 complex between asplatin and PSC4 is formed. The stability constant of the designed complex has been determined using Job's plot and UHPLC and computed to be 9.1 × 104 M-1 and 8.7 × 104 M-1, which corresponds to a free energy of complexation of -6.8 kcal mol-1, while the calculated value for the inclusion free energy is -13.2 kcal mol-1. Both experimentally and theoretically estimated complexation free energy show that a stable host-guest complex can be formed in solution. The in vitro drug release study displayed the ability of the complex to release its cargo at a cancerous pH (pH of 5.5). Additionally, the asplatin/PSC4 complex is shown to be biocompatible when tested on human skin fibroblast noncancerous cells, demonstrating the highest in vitro cytotoxic activity against (MCF-7), cervical (HeLa), and lung cancer cells (A-549), with IC50 values of 0.75, 2.15, and 3.60 µg/mL, respectively. This is as compared to either cisplatin (IC50 of 5.47, 5.94 and 9.61 µg/mL, respectively) or asplatin (IC50 of 1.54, 5.05 and 3.91 µg/mL, respectively). On the other hand, the free asplatin exhibited higher cytotoxicity on cancerous cells and lower toxicity on noncancerous cells. The outcomes of the present joint theoretical and experimental investigation reinforce the interest in platinum-based anticancer therapeutics when they are protected from undesired interactions and suggest the use of the PSC4 macromolecule as a promising carrier for Pt(IV) anticancer drugs. The formed asplatin/PSC4 inclusion complex may represent an effective chemotherapeutic agent.

PEGylated Chitosan Nanoparticles Encapsulating Ascorbic Acid and Oxaliplatin Exhibit Dramatic Apoptotic Effects against Breast Cancer Cells.

This study aims to design a pH-responsive dual-loaded nanosystem based on PEGylated chitosan nanoparticles loaded with ascorbic acid (AA) and oxaliplatin (OX) for the effective treatment of breast cancer. In this regard, non-PEGylated and PEGylated chitosan nanoparticles (CS NPs) loaded with either ascorbic acid (AA), oxaliplatin (OX), or dual-loaded with AA-OX were fabricated using the ionotropic gelation method. The hydrodynamic diameters of the fabricated AA/CS NPs, OX/CS NPs, and AA-OX/CS NPs were 157.20 ± 2.40, 188.10 ± 9.70, and 261.10 ± 9.19 nm, respectively. While the hydrodynamic diameters of the designed AA/PEG-CS NPs, OX/PEG-CS NPs, and AA-OX/PEG-CS NPs were 152.20 ± 2.40, 156.60 ± 4.82, and 176.00 ± 4.21 nm, respectively. The ζ-potential of the prepared nanoparticles demonstrated high positive surface charges of +22.02 ± 1.50, +22.58 ± 1.85 and +40.4 ± 2.71 mV for AA/CS NPs, OX/CS NPs, and AA-OX/CS NPs, respectively. The ζ-potential of the PEGylated CS NPs was reduced owing to the shielding of the positive charges by the PEG chains. Additionally, all the prepared nanoparticles exhibited high entrapment efficiencies (EE%) and spherical-shaped morphology. The chemical features of the prepared nanoparticles were investigated using Fourier transform infrared (FTIR) spectroscopy. Release studies showed the capability of the prepared non-PEGylated and PEGylated chitosan NPs to release their cargo in the acidic environment of cancer tissue (pH 5.5). Furthermore, the AA/CS NPs, AA/PEG-CS NPs, OX/CS NPs, OX/PEG-CS NPs, AA-OX/CS NPs and AA-OX/PEG-CS NPs exhibited remarkable cytotoxic activities against breast adenocarcinoma (MCF-7) cells with IC50 values of 44.87 ± 11.49, 23.3 ± 3.73, 23.88 ± 6.29, 17.98 ± 3.99, 18.69 ± 2.22, and 7.5 ± 0.69 µg/mL, respectively; as compared to free AA and OX (IC50 of 150.80 ± 26.50 and 147.70 ± 63.91 µg/mL, respectively). Additionally, treatment of MCF-7 cells with IC50 concentrations of AA, AA/CS NPs, AA/PEG-CS NPs, OX, OX/CS NPs, OX/PEG-CS NPs, AA-OX/CS NPs or AA-OX/PEG-CS NPs increased the percentages of early apoptotic cells to 5.28%, 9.53%, 11.20%, 5.27%, 13.80%, 8.43%, 2.32%, and 10.10%, respectively, and increased the percentages of late apoptotic cells to 0.98%, 0.37%, 2.41%, 2.06%, 0.97%, 9.66%, 56%, and 81.50%, respectively. These results clearly indicate that PEGylation enhances the apoptotic effect of AA and OX alone, in addition to potentiating the apoptotic effect of AA and OX when combined on MCF-7 cells. In conclusion, PEGylated chitosan nanoparticles encapsulating AA, OX, or AA and OX represent an effective formula for induction of apoptosis in MCF-7 cells.

Design and Synthesis of New CDK2 Inhibitors Containing Thiazolone and Thiazolthione Scafold with Apoptotic Activity.

Cyclin dependent kinase 2 (CDK2) inhibition is a well-established strategy for treating cancer. Different series of novel thiazolone (1, 7-9) together with fused thiazolthione (2-6, and 10) derivatives were designed, then synthesized and evaluated for their biological inhibitory activity against CDK2. Additionally, the cytotoxicity of the new compounds was explored against breast and colon cancer cell lines. The novel thiazolone and the fused thiazolthione derivatives exhibited potent CDK2/cyclin A2 inhibitory effect of an IC50 values ranging 105.39-742.78 nM. Amongst them compounds 4 and 6 revealed highest IC50 of 105.39 and 139.27 nM, respectively. Most compounds showed significant inhibition on both breast cancer and colon cancer cell lines with IC50 range 0.54-5.26 and 0.83-278 µM, respectively. Further investigations involved flow cytometry analysis on MCF-7 cancer cell line for compounds 5 and 7 which resulted in arrest cell-cycle at two phases Pre G1/G2-M and re-enforced apoptosis via activation of caspase-7. Molecular modeling simulation of the designed compounds revealed that they were well fitted into CDK2 active site and their complexes were stabilized through the essential hydrogen bonding. Three dimensional quantitative structure activity relationship (3D QSAR) pharmacophore, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were also carried out showing proper pharmacokinetic and drug-likeness which aided in the prediction of the structure requirements responsible for the observed antitumor activity.

Design, synthesis, docking study and anticancer evaluation of new trimethoxyphenyl pyridine derivatives as tubulin inhibitors and apoptosis inducers.

Microtubules have become an appealing target for anticancer drug development including mainly colchicine binding site inhibitors (CBSIs). A new series of novel trimethoxypyridine derivatives were designed and synthesized as tubulin targeting agents. In vitro anti-proliferative activities of the tested compounds compared to colchicine against hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116), and breast cancer (MCF-7) was carried out. Most of compounds showed significant cytotoxic activities. Compounds Vb, Vc, Vf, Vj and VI showed superior anti-proliferative activities to colchicine. Where compound VI showed IC50 values of 4.83, 3.25 and 6.11 µM compared to colchicine (7.40, 9.32, 10.41 µM) against HCT 116, HepG-2 and MCF-7, respectively. The enzymatic activity against tubulin enzyme was carried out for the compounds that showed high anti-proliferative activity. Also, compound VI exhibited the highest tubulin polymerization inhibitory effect with an IC50 value of 8.92 nM compared to colchicine (IC50 value = 9.85 nM). Compounds Vb, Vc, Vf, Vj, & VIIIb showed promising activities with IC50 values of 22.41, 17.64, 20.39, 10.75, 31.86 nM, respectively. Cell cycle and apoptosis test for compound VI against HepG-2 cells, indicated that compound VI can arrest cell cycle at G2/M phase, and can cause apoptosis at pre-G1 phase, with high apoptotic effect 18.53%. Molecular docking studies of the designed compounds confirmed the essential hydrogen bonding with CYS241 beside the hydrophobic interaction at the binding site compared to reference compounds which assisted in the prediction of the structure requirements for the detected antitumor activity.