Synthesis and evaluation of pyridine-3-carboxamide analogs as effective agents against bacterial wilt in tomatoes.

This study focused on developing novel pyridine-3-carboxamide analogs to treat bacterial wilt in tomatoes caused by Ralstonia solanacearum. The analogs were synthesized through a multistep process and their structures confirmed using spectroscopy. Molecular docking studies identified the most potent analog from the series. A specific analog, compound 4a, was found to significantly enhance disease resistance in tomato plants infected with R. solanacearum. The structure-activity relationship analysis showed the positions and types of substituents on the aromatic rings of compounds 4a-i strongly influenced their biological activity. Compound 4a, with a chloro group at the para position on ring C and hydroxyl group at the ortho position on ring A, was exceptionally effective against R. solanacearum. When used to treat seeds, the analogs displayed remarkable efficacy, especially compound 4a which had specific activity against bacterial wilt pathogens. Compound 4a also promoted vegetative and reproductive growth of tomato plants, increasing seed germination and seedling vigor. In plants mechanically infected with bacteria, compound 4a substantially reduced the percentage of infection, pathogen quantity in young tissue, and disease progression. The analogs were highly potent due to their amide linkage. Molecular docking identified the best compounds with strong binding affinities. Overall, the strategic design and synthesis of these pyridine-3-carboxamide analogs offers an effective approach to targeting and controlling R. solanacearum and bacterial wilt in tomatoes.

Sinefungin analogs targeting VP39 methyltransferase as potential anti-monkeypox therapeutics: a multi-step computational approach.

The increasing spread of the Monkeypox virus (MPXV) presents a significant public health challenge, emphasising the urgent requirement for effective treatments. Our study focuses on the VP39 Methyltransferase enzyme of MPXV as a critical target for therapy. By utilising virtual screening, we investigated natural compounds with structural similarities to sinefungin, a broad-acting MTase inhibitor. From an initial set of 177 compounds, we identified three promising compounds-CNP0346326, CNP0343532, and CNP008361, whose binding scores were notably close to that of sinefungin. These candidates bonded strongly to the VP39 enzyme, hinting at a notable potential to impede the virus. Our rigorous computational assays, including re-docking, extended molecular dynamics simulations, and energetics analyses, validate the robustness of these interactions. The data paint a promising picture of these natural compounds as front-runners in the ongoing race to develop MPXV therapeutics and set the stage for subsequent empirical trials to refine these discoveries into actionable medical interventions.

Investigating the bispecific lead compounds against methicillin-resistant Staphylococcus aureus SarA and CrtM using machine learning and molecular dynamics approach.

Methicillin-resistant Staphylococcus aureus (MRSA) is a notorious pathogen that has emerged as a serious global health concern over the past few decades. Staphylococcal accessory regulator A (SarA) and 4,4'-diapophytoene synthase (CrtM) play a crucial role in biofilm formation and staphyloxanthin biosynthesis. Thus, the present study used a machine learning-based QSAR model to screen 1261 plant-derived natural organic compounds in order to identify a medication candidate with both biofilm and virulence inhibitory potential. Additionally, the in-silico molecular docking analysis has demonstrated significant binding efficacy of the identified hit compound, that is 85137543, with SarA and CrtM when compared to the control compound, hesperidin. Post-MD simulation analysis of the complexes depicted strong binding of 85137543 to both SarA and CrtM. Moreover, 85137543 showed hydrogen bonding with the key residues of both proteins during docking (ALA138 of SarA and ALA134 of CrtM) and post-MD simulation (LYS273 of CrtM and ASN212 of SarA). The RMSD of 85137543 was stable and consistent when bound to both CrtM and SarA with RMSDs of 1.3 and 1 nm, respectively. In addition, principal component analysis and the free energy landscape showed stable complex formation with both proteins. Low binding free energy (ΔGTotal) was observed by 85137543 for SarA (-47.92 kcal/mol) and CrtM (-36.43 kcal/mol), which showed strong binding. Overall, this study identified 85137543 as a potential inhibitor of both SarA and CrtM in MRSA.Communicated by Ramaswamy H. Sarma.

Isoform switching leads to downregulation of cytokine producing genes in estrogen receptor positive breast cancer.

Objective: Estrogen receptor breast cancer (BC) is characterized by the expression of estrogen receptors. It is the most common cancer among women, with an incidence rate of 2.26 million cases worldwide. The aim of this study was to identify differentially expressed genes and isoform switching between estrogen receptor positive and triple negative BC samples. Methods: The data were collected from ArrayExpress, followed by preprocessing and subsequent mapping from HISAT2. Read quantification was performed by StringTie, and then R package ballgown was used to perform differential expression analysis. Functional enrichment analysis was conducted using Enrichr, and then immune genes were shortlisted based on the ScType marker database. Isoform switch analysis was also performed using the IsoformSwitchAnalyzeR package. Results: A total of 9,771 differentially expressed genes were identified, of which 86 were upregulated and 117 were downregulated. Six genes were identified as mainly associated with estrogen receptor positive BC, while a novel set of ten genes were found which have not previously been reported in estrogen receptor positive BC. Furthermore, alternative splicing and subsequent isoform usage in the immune system related genes were determined. Conclusion: This study identified the differential usage of isoforms in the immune system related genes in cancer cells that suggest immunosuppression due to the dysregulation of CXCR chemokine receptor binding, iron ion binding, and cytokine activity.

Green Synthesis of Zinc Oxide Nanoparticles Using Cymbopogon citratus Extract and Its Antibacterial Activity.

Excessive use of antimicrobial medications including antibiotics has led to the emerging menace of antimicrobial resistance, which, as per the World Health Organization (WHO), is among the top ten public health threats facing humanity, globally. This necessitates that innovative technologies be sought that can aid in the elimination of pathogens and hamper the spread of infections. Zinc oxide (ZnO) has multifunctionality owing to its extraordinary physico-chemical properties and functionality in a range of applications. In this research, ZnO nanoparticles (NPs) were synthesized from zinc nitrate hexahydrate, by a green synthesis approach using Cymbopogon citratus extract followed by characterization of the NPs. The obtained X-ray diffraction peaks of ZnO NPs matched with the standard JCPDS card (no. 89-510). The particles had a size of 20-24 nm, a wurtzite structure with a high crystallinity, and hexagonal rod-like shape. UV-Vis spectroscopy revealed absorption peaks between 369 and 374 nm of ZnO NPs synthesized from C. citratus extract confirming the formation of ZnO. Fourier transform infrared confirmed the ZnO NPs as strong absorption bands were observed in the range of 381-403 cm-1 corresponding to Zn-O bond stretching. Negative values of the highest occupied molecular orbital-lowest unoccupied molecular orbital for ZnO NPs indicated the good potential to form a stable ligand-protein complex. Docking results indicated favorable binding interaction between ZnO and DNA gyrase subunit b with a binding energy of -2.93 kcal/mol. ZnO NPs at various concentrations inhibited the growth of Escherichia coli and Staphylococcus aureus. Minimum inhibitory concentration values of ZnO NPs against E. coli and S. aureus were found to be 92.07 ± 0.13 and 88.13 ± 0.35 µg/mL, respectively, at a concentration of 2 mg/mL. AO/EB staining and fluorescence microscopy revealed the ability of ZnO NPs to kill E. coli and S. aureus cells. Through the findings of this study, it has been shown that C. citratus extract can be used in a green synthesis approach to generate ZnO NPs, which can be employed as alternatives to antibiotics and a tool to eliminate drug-resistant microbes in the future.

Novel landmarks on the journey from natural products to pharmaceutical formulations: Phytochemical, biological, toxicological and computational activities of Satureja hortensis L.

This study examined the ethanolic extract of the Satureja hortensis L. plant's aerial parts to describe its phytochemical makeup, biological functions, toxicity tests, and in-silico molecular docking tests. The GC-MS analysis was used to evaluate the phytochemical composition of the tested extract, and the ABTS and hydrogen peroxide antioxidant assays were used to measure antioxidant activity. Aspergillus fumigatus, Candida albicans, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Proteus vulgaris were tested for antimicrobial potential. On cell lines such as HepG-2, MCF-7, A-549, and Panc-1, the in-vitro toxicity was also examined. The A-549 cell line was also used for flow cytometry analysis of apoptosis and cell cycle. Additionally, the compounds discovered by the GC-MS analysis were used in silico tests against biological targets. Eight different phytocompounds were tentatively identified as a result of the GC-MS analysis. The compounds also demonstrated significant antioxidant potential for the ABTS and H2O2 assays (IC50: 2.44 and 28.04 µg/ml, respectively). The tested extract was found to have a range of inhibition zones and to be significantly active against the tested bacterial and fungal strains. Apoptosis and cell cycle analysis for the A-549 cell line showed that the cell cycle was arrested at S-phase, and the extract was also found to be most active against this cell line with an IC50 value of 113.05 µg/ml. The docking studies have emphasized the compounds' interactions and binding scores with the EGFR-TK target as determined by the GC-MS.

Synthesis, Crystal Structure, Antibacterial and In Vitro Anticancer Activity of Novel Macroacyclic Schiff Bases and Their Cu (II) Complexes Derived from S-Methyl and S-Benzyl Dithiocarbazate.

A series of novel macroacyclic Schiff base ligands and their Cu (II) complexes were synthesised via reacting dicarbonyls of varying chain lengths with S-methyl dithiocarbazate (SMDTC) and S-benzyl dithiocarbazate (SBDTC) followed by coordination with Cu (II) ions. X-ray crystal structures were obtained for compound 4, an SBDTC-diacetyl analogue, and Cu7, an SMDTC-hexanedione Cu (II) complex. Anticancer evaluation of the compounds showed that Cu1, an SMDTC-glyoxal complex, demonstrated the highest cytotoxic activity against MCF-7 and MDA-MB-231 breast cancer cells with IC50 values of 1.7 µM and 1.4 µM, respectively. There was no clear pattern observed between the effect of chain length and cytotoxic activity; however, SMDTC-derived analogues were more active than SBDTC-derived analogues against MDA-MB-231 cells. The antibacterial assay showed that K. rhizophila was the most susceptible bacteria to the compounds, followed by S. aureus. Compound 4 and the SMDTC-derived analogues 3, 5, Cu7 and Cu9 possessed the highest antibacterial activity. These active analogues were further assessed, whereby 3 possessed the highest antibacterial activity with an MIC of <24.4 µg/mL against K. rhizophila and S. aureus. Further antibacterial studies showed that at least compounds 4 and 5 were bactericidal. Thus, Cu1 and 3 were the most promising anticancer and antibacterial agents, respectively.

Manufacturing of Corrosion Inhibitors and Flow Improvers from Recycling of Waste at Hail City, Saudi Arabia: Physicochemical and Electrochemical Studies on Steel in Petroleum Industries.

The aim of the present research paper is to convert daily waste materials generated by human activity at Hail city into useful petroleum additives. In this respect, novel multifunctional corrosion inhibitors working as inhibitors and flow improvers for crude oil were prepared. Polyethylene terephthalate (PET) plastic waste is used in the production of corrosion inhibitors and flow improvers for petroleum crude oil. A multifunctional corrosion inhibitor for the SABIC carbon steel in corrosive seawater for application in the petroleum industry was manufactured using PET waste that was gathered, cleaned, and used as starting materials. The PET green recycling method takes place via the Abdel-Hameed green recycling reported method. In the first step, PET waste was reacted without a solvent with a diamine to form the diamino derivative of phthalic acid amide (PETAA), which was characterized by FT-IR, 1HNMR, and elemental analysis. In the presence of a catalyst, the used recycling method is a solvent-free green recycling process that is environmentally friendly. Chemical and electrochemical measurements were performed, and the effects of concentration and temperature were studied. The inhibition efficiency was found to increase with concentration. A maximum inhibition of 97% was obtained using 4000 ppm from the prepared PETAA inhibitor, while the efficiency decreased with temperature. Potentiodynamic polarization (PDP) data indicates the mixed-type nature of the used inhibitor. According to potentiodynamic polarization data, the inhibitor boosts polarization resistance and inhibition performance by adsorbing on the metal/electrolyte interface. The data from electrochemical impedance spectroscopy (EIS) show that the charge-transfer mechanism is the primary governing factor in the steel dissolution process. The size of the semicircle grows in direct proportion to the concentration of the inhibitor. The prepared additive acts as a flow improver (viscosity improvers and pour point depressants) for waxy crude oil, indicating that it can be used in the manufacturing of multifunctional inhibitors in the petroleum industry. The depression in the pour point temperatures depended on the concentration and composition of the additive prepared from the plastic waste collected from Hail city.

Design, Synthesis, Characterization and Computational Studies of Mannich Bases Oxadiazole Derivatives as New Class of Jack Bean Urease Inhibitors.

Mannich bases consisting of 1,3,4-oxadiazole-2-thione (3 a-3 l) bearing various substituents were synthesized and found potent jack bean urease inhibitors. The prepared compounds showed significantly good inhibitory activities with IC50 values from 9.45±0.05 to 267.42±0.23 µM. The compound 3 k containing 4-chlorophenyl (-R) and 4-hydroxyphenyl (-R') was most active with IC50 9.45±0.05 µM followed by 3 e (IC50 22.52±0.15 µM) in which -R was phenyl and -R' was isopropyl group. However, when both -R and -R' were either 4-chlorophenyl groups (3 l) or only -R' was 4-nitrophenyl (3 i), both compounds were found inactive. The detailed binding affinities of the produced compounds with protein were explored through molecular docking and data-supported in-vitro enzyme inhibition profiles. Drug likeness was confirmed by in silico ADME investigations and molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps were got from DFT calculations. ESP maps exposed that there are two potential binding sites with the most positive and most negative parts.

Evaluating the Counseling Standards and Ability of Pharmacy Staff to Detect Antibiotic-Drugs Interactions: A Simulated Client Study from Pakistan.

Effective and safe medication use can be maximized by providing medication counseling, which aims to optimize therapeutic results. This approach improves the effectiveness of antibacterial treatment, reduces treatment expenses, and mitigates the emergence of antimicrobial resistance. No research from Pakistan has been previously documented. The purpose of this research was to evaluate both the quality of antibiotic counseling provided and the level of understanding exhibited by pharmacy employees with regard to interactions involving antibiotic medications. Using a simulated client method, two scenarios were used to assess 562 pharmacies that were systematically selected. Scenario 1 focused the counseling for use of prescribed medicines with non-prescribed antibiotics. Scenario2 indicated counseling provision for prescribed antibiotics that have possible antibiotic-drug interactions. The evaluation of counseling skills was also conducted. The analysis involved the use of descriptive statistics and chi-square tests. Only 34.1% of simulated clients received medication counseling directly; 45% received it on request. About 31.2% of clients were referred to a physician without counseling. The most frequently provided information was therapy dose (81.6%) and duration (57.4%). More than half (54.0%) of clients were asked about disease duration, but drug storage was ignored. Insufficient information was provided about side effects (1.1%) and antibiotic-drug interactions (1.4%). Most (54.3%) clients were instructed about dietary or lifestyle modifications. Only 1.9% of clients received information about drug administration route. No information was provided about other medication during therapy, effect of medicine withdrawal, and compliance to medication. The current level of antibiotic counseling within Pakistani community pharmacies is inadequate and requires the attention of medical authorities. Professional training of staff could improve counseling.

Artemisia sieberi Besser essential oil inhibits the growth and migration of breast cancer cells via induction of S-phase arrest, caspase-independent cell death and downregulation of ERK.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia sieberi Besser is a medicinal herb that has been traditionally used across the Middle East for the treatment of cancer. Further pharmacological studies on its extracts revealed that they possess cytotoxic activity against certain cancer cells, however, there were no studies conducted on the anticancer potential of Artemisia sieberi essential oil (ASEO). AIM OF THE STUDY: To evaluate the anticancer potential of ASEO, elucidate the oil's mode of action for the first time and investigate its chemical composition. MATERIALS AND METHODS: Artemisia sieberi was collected from Hail, Saudi Arabia, and its essential oil was obtained via hydrodistillation. The oil's activity against HCT116, HepG2, A549 and MCF-7 cells was assessed using SRB assay, while its anti-metastatic potential was assessed via a migration assay. Cell-cycle analysis and apoptosis assay were conducted via flow cytometry, while protein expression levels were investigated using Western blotting. The oil's chemical constituents were identified using GCMS. RESULTS: ASEO exerted its highest cytotoxic activity against MCF-7 with an IC50 value of 38.7 µg/ml. Further studies showed that the oil inhibited MCF-7 cells' migration, induced S-phase arrest and apoptosis. Western blot analysis showed no change in the expression level of caspase-3 after treatment, indicating the induction of caspase-independent apoptosis-like cell death in MCF-7. Treatment of MCF-7 with the oil resulted in downregulation of the protein expression levels of total ERK and its downstream target, LC3, indicating that any potential activation of the ERK signalling pathway during the cancer cells' growth would be inhibited. Finally, GCMS analysis identified the oil's major components as cis-crysanthenyl acetate (48.56%), davanone (10.28%), 1,8-cineole (6.81%) and caryophyllene diepoxide (5.34%), whereby it is suggested that these compounds might be responsible for the oil's bioactivity. CONCLUSION: ASEO possessed in vitro anticancer activity and modulated the ERK signalling pathway. This is the first study to explore the anticancer potential of ASEO in detail and reflects the significance of investigating essential oils from medicinal plants that have been traditionally used against cancer. This work might pave the way for further in vivo studies that could result in developing the oil into a natural effective anticancer treatment.

Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold.

Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor-associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development.

Chemical Composition, Antibacterial Activity and In Vitro Anticancer Evaluation of Ochradenus baccatus Methanolic Extract.

Background and Objectives: Ochradenus baccatus belongs to the family Resedaceae. It is widely spread in Saudi Arabia and other countries in Southwest Asia. O. baccatus is extensively used in traditional medicine as an anti-inflammatory and antibacterial agent, in addition to being a vital source of food for certain desert animal species. The aim of the present study was to investigate the chemical composition and antibacterial/anticancer activities of O. baccatus methanolic extracts collected from Hail, Saudi Arabia. Materials and Methods: The O. baccatus extracts were obtained by macerating the crude powder in methanol, followed by filtration and evaporation. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the methanolic extracts' chemical constituents. Broth microdilution assay for minimum inhibitory concentration (MIC) determination was used to assess antimicrobial activity, while the extracts' anticancer potential was assessed by sulforhodamine B Assay (SRB) assay. Results: The results of the antibacterial assay showed that the methanolic extracts from the roots and branches possessed varying degrees of activity against particular bacterial strains, with the highest activity being exerted by the branches' extract against Escherichia coli and Salmonella typhimurium (St), demonstrating MIC values of 15.6 µg/mL and 20 µg/mL, respectively. Furthermore, the SRB cell viability assay revealed that only the branches' extract inhibited the growth of A549 cancer cells, with an IC50 value of 86.19 µg/mL. The LC-MS analysis of the methanolic extracts from the plant's roots and branches was then conducted, resulting in the identification of 8 and 13 major chemical constituents, respectively. Azelaic acid, ß-amyrin, and phytanic acid are some of the bioactive compounds that were detected in the extracts via LC-MS, and they are thought to be responsible for the observed antibacterial/anticancer activity of O. baccatus methanolic extracts. Conclusions: This study confirmed the antibacterial/anticancer potential of O. baccatus methanolic extracts and analyzed their phytochemical constituents. Further isolation and biological screening are warranted to understand the therapeutic potential of O. baccatus.

Microwave assisted synthesis of 2-amino-4-chloro-pyrimidine derivatives: Anticancer and computational study on potential inhibitory action against COVID-19.

We report microwave synthesis of seven unique pyrimidine anchored derivatives (1-7) incorporating multifunctional amino derivatives along with their in vitro anticancer activity and their activity against COVID-19 in silico. 1-7 were characterized by different analytical and spectroscopic techniques. Cytotoxic activity of 1-7 was tested against HCT116 and MCF7 cell lines, whereby 6 exhibited highest anticancer activity on HCT116 and MCF7 with EC50 values of 89.24 ± 1.36 µM and 89.37 ± 1.17 µM, respectively. Molecular docking was performed for derivatives (1-7) on main protease for SARS-CoV-2 (PDB ID: 6LU7). Results revealed that most of the derivatives had superior or equivalent affinity for the 3CLpro, as determined by docking and binding energy scores. 6 topped the rest with highest binding energy score of -8.12 kcal/mol with inhibition constant reported as 1.11 µM. ADME, drug-likeness, and pharmacokinetics properties of 1-7 were tested using Swiss ADME tool. Toxicity analysis was done with pkCSM online server. All derivatives showed high GI absorption. Except 1 and 3, all derivatives showed blood brain barrier permeability. Most derivatives showed negative logKp values suggesting derivatives are less skin permeable and bioavailability score of all derivatives was 0.55. The toxicity analysis demonstrated that all derivatives have no skin sensitization properties. 6 and 7 showed maximum tolerated dose (Human) values of -0.03 and -0.018, respectively and absence of AMES toxicity.

Manganese chloride (MnCl2) induced novel model of Parkinson's disease in adult Zebrafish; Involvement of oxidative stress, neuroinflammation and apoptosis pathway.

Parkinson's disease (PD) is a progressive neurodegenerative disorder imposing a severe health and socioeconomic burden worldwide. Existing pharmacological approaches for developing PD are poorly developed and do not represent all the characteristics of disease pathology. Developing cost-effective, reliable Zebrafish (ZF) model will meet this gap. The present study was conceived to develop a reliable PD model in the ZF using manganese chloride (MnCl2). Here, we report that chronic exposure to 2 mM MnCl2 for 21 days produced non-motor and motor PD-like symptoms in adult ZF. Compared with control fish, MnCl2-treated fish showed reduced locomotory activity, indicating a deficit in motor function. In the light-dark box test, MnCl2-treated fish exhibited anxiety and depression-like behavior. MnCl2-treated fish exhibited a less olfactory preference for amino acids, indicating olfactory dysfunction. These behavioral symptoms were associated with decreased dopamine and increased DOPAC levels. Furthermore, oxidative stress-mediated apoptotic pathway, decreased brain derived neurotropic factor (BDNF) and increased pro-inflammatory cytokines levels were observed upon chronic exposure to MnCl2 in the brain of ZF. Thus, MnCl2-induced PD in ZF can be a cost-effective PD model in the drug discovery process. Moreover, this model could be potentially utilized to investigate the molecular pathways underlying the multifaceted pathophysiology which leads to PD using relatively inexpensive species. MnCl2 being heavy metal may have other side effects in addition to neurotoxicity. Our model recapitulates most of the hallmarks of PD, but not all pathological processes are involved. Future studies are required to recapitulate the complete pathophysiology of PD.

Development of GBRT Model as a Novel and Robust Mathematical Model to Predict and Optimize the Solubility of Decitabine as an Anti-Cancer Drug.

The efficient production of solid-dosage oral formulations using eco-friendly supercritical solvents is known as a breakthrough technology towards developing cost-effective therapeutic drugs. Drug solubility is a significant parameter which must be measured before designing the process. Decitabine belongs to the antimetabolite class of chemotherapy agents applied for the treatment of patients with myelodysplastic syndrome (MDS). In recent years, the prediction of drug solubility by applying mathematical models through artificial intelligence (AI) has become known as an interesting topic due to the high cost of experimental investigations. The purpose of this study is to develop various machine-learning-based models to estimate the optimum solubility of the anti-cancer drug decitabine, to evaluate the effects of pressure and temperature on it. To make models on a small dataset in this research, we used three ensemble methods, Random Forest (RFR), Extra Tree (ETR), and Gradient Boosted Regression Trees (GBRT). Different configurations were tested, and optimal hyper-parameters were found. Then, the final models were assessed using standard metrics. RFR, ETR, and GBRT had R2 scores of 0.925, 0.999, and 0.999, respectively. Furthermore, the MAPE metric error rates were 1.423 × 10-1 7.573 × 10-2, and 7.119 × 10-2, respectively. According to these facts, GBRT was considered as the primary model in this paper. Using this method, the optimal amounts are calculated as: P = 380.88 bar, T = 333.01 K, Y = 0.001073.

In Silico Pharmacokinetic Profiling of the Identified Bioactive Metabolites of Pergularia tomentosa L. Latex Extract and In Vitro Cytotoxic Activity via the Induction of Caspase-Dependent Apoptosis with S-Phase Arrest.

The in vitro cytotoxic efficacy of plant latex from Pergularia tomentosa L. was studied using five human cancer cell lines: HeLa cells (cervical carcinoma cells), A-549 (lung carcinoma), Panc-1 (pancreatic carcinoma cells), MDA-MB-231 (metastatic mammary adenocarcinoma), and MRC-5 (lung fibroblast cell line) cells. The phytonutrient content of plant latex was identified using the liquid chromatography/mass spectra-quadrupole time of flight (LC/MS-QTOF) technique. In silico studies of polyphenols were carried out to clarify the potential mode of action of the plant latex's constituents. The treatment of different tumor cell lines with different concentrations of plant latex revealed a potent efficacy on the human lung carcinoma cell line (A-549) (IC50 = 3.89 µg/mL) compared with that with vinblastine as a positive control (IC50 = 7.12 µg/mL). The effect of the potent concentration of plant latex on the A-549 cell line induced cell arrest, upregulated the expression of pre-apoptotic markers, and downregulated the expression of antiapoptotic markers. Seven identified polyphenols were selected for the in silico study. A docking assessment using the epidermal growth factor receptor kinase (EGFRk) and eltronib as a positive control showed a higher affinity for the enzyme receptor of the selected polyphenols, except for methyl orsellinate and ginkgotoxin. The ADMET assessment demonstrated the inhibitory effect of the polyphenols on CYP450, except for ouabagenin and xanthyletine. The selected polyphenols obey Lipinski's drug-likeness with no significant toxicity effect. In conclusion, the plant latex of P. tomentosa L. showed cytotoxic activity on the A-549 cell line, and the selected polyphenols showed a promising prodrug agent with a low profile of toxicity in the study.

Fabrication, In Vitro, and In Vivo Assessment of Eucalyptol-Loaded Nanoemulgel as a Novel Paradigm for Wound Healing.

Wounds are the most common causes of mortality all over the world. Topical drug delivery systems are more efficient in treating wounds as compared to oral delivery systems because they bypass the disadvantages of the oral route. The aim of the present study was to formulate and evaluate in vitro in vivo nanoemulgels loaded with eucalyptol for wound healing. Nanoemulsions were prepared using the solvent emulsification diffusion method by mixing an aqueous phase and an oil phase, and a nanoemulgel was then fabricated by mixing nanoemulsions with a gelling agent (Carbopol 940) in a 1:1 ratio. The nanoemulgels were evaluated regarding stability, homogeneity, pH, viscosity, Fourier-transform infrared spectroscopy (FTIR), droplet size, zeta potential, polydispersity index (PDI), spreadability, drug content, in vitro drug release, and in vivo study. The optimized formulation, F5, exhibited pH values between 5 and 6, with no significant variations at different temperatures, and acceptable homogeneity and spreadability. F5 had a droplet size of 139 ± 5.8 nm, with a low polydispersity index. FTIR studies showed the compatibility of the drug with the excipients. The drug content of F5 was 94.81%. The percentage of wound contraction of the experimental, standard, and control groups were 100% ± 0.015, 98.170% ± 0.749, and 70.846% ± 0.830, respectively. Statistically, the experimental group showed a significant difference (p < 0.03) from the other two groups. The results suggest that the formulated optimized dosage showed optimum stability, and it can be considered an effective wound healing alternative.

Anti-Cancer Drug Solubility Development within a Green Solvent: Design of Novel and Robust Mathematical Models Based on Artificial Intelligence.

Nowadays, supercritical CO2(SC-CO2) is known as a promising alternative for challengeable organic solvents in the pharmaceutical industry. The mathematical prediction and validation of drug solubility through SC-CO2 system using novel artificial intelligence (AI) approach has been considered as an interesting method. This work aims to evaluate the solubility of tamoxifen as a chemotherapeutic drug inside the SC-CO2 via the machine learning (ML) technique. This research employs and boosts three distinct models utilizing Adaboost methods. These models include K-nearest Neighbor (KNN), Theil-Sen Regression (TSR), and Gaussian Process (GPR). Two inputs, pressure and temperature, are considered to analyze the available data. Furthermore, the output is Y, which is solubility. As a result, ADA-KNN, ADA-GPR, and ADA-TSR show an R2 of 0.996, 0.967, 0.883, respectively, based on the analysis results. Additionally, with MAE metric, they had error rates of 1.98 × 10-6, 1.33 × 10-6, and 2.33 × 10-6, respectively. A model called ADA-KNN was selected as the best model and employed to obtain the optimum values, which can be represented as a vector: (X1 = 329, X2 = 318.0, Y = 6.004 × 10-5) according to the mentioned metrics and other visual analysis.

Rapid oral transmucosal delivery of zaleplon-lavender oil utilizing self-nanoemulsifying lyophilized tablets technology: development, optimization and pharmacokinetic evaluation.

Based on the administration convenience, transmucosal buccal drug delivery allows special strength points over peroral routes for systemic delivery. It could achieve local or systemic effect and boost drugs' bioavailability for agents with first pass metabolism. The current study aimed to manufacture and optimize a lavender oil-based nanoemulsion loaded with zaleplon and incorporate it into fast-disintegrating tablets to promote its dissolution and oral bioavailability via oral mucosa. Zaleplon-loaded nanoemulsions were devised with various levels of lavender oil (10% to 25%), the surfactant Sorbeth-20 (35% to 65%), and the co-surfactant HCO-60 (20% to 40%); the extreme vertices mixture statistical design was adopted. The droplet size and drug-loading efficiency were the evaluated. The optimal formulation was transformed into self-nanoemulsified lyophilized tablets (ZP-LV-SNELTs), which were tested for their uniformity of content, friability, and disintegration time with in-vitro release. Finally, the pharmacokinetic parameters of the ZP-LV-SNELTs were determined and compared with those of marketed formulations. The optimal nanoemulsion had a droplet size of 87 nm and drug-loading capacity of 185 mg/mL. ZP-LV-SNELTs exhibited acceptable friability and weight uniformity and a short disintegration time. The in-vitro release of ZP-LV-SNELTs was 17 times faster than that of the marketed tablet. Moreover, the optimal ZP-LV-SNELTs increased the bioavailability of zaleplon in rabbits by 1.6-fold compared with the commercial tablets. Hence, this investigation revealed that ZP-LV-SNELTs delivered zaleplon with enhanced solubility, a fast release, and boosted bioavailability thru oral mucosa which provided a favorable route for drug administration which is suggested to be clinically investigated in future studies.