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Abstract This study provides an in-depth examination of forecasting the concentration of pharmaceutical compounds utilizing the input features (coordinates) r and z through a range of machine learning models. Purification of pharmaceuticals via vacuum membrane distillation process was carried out and the model was developed for prediction of separation efficiency based on hybrid approach. Dataset was collected from mass transfer analysis of process to obtain concentration distribution in the feed side of membrane distillation and used it for machine learning models. The dataset has undergone preprocessing, which includes outlier detection using the Isolation Forest algorithm. Three regression models were used including polynomial regression (PR), k-nearest neighbors (KNN), and Tweedie regression (TWR). These models were further enhanced using the Bagging ensemble technique to improve prediction accuracy and reduce variance. Hyper-parameter optimization was conducted using the Multi-Verse Optimizer algorithm, which draws inspiration from cosmological concepts. The Bagging-KNN model had the highest predictive accuracy (R2 = 0.99923) on the test set, indicating exceptional precision. The Bagging-PR model displayed satisfactory performance, with a slightly reduced level of accuracy. In contrast, the Bagging-TWR model showcased the least accuracy among the three models. This research illustrates the effectiveness of incorporating bagging and advanced optimization methods for precise and dependable predictive modeling in complex datasets.

Recent decades have seen a shortage of water, which has led scientists to concentrate on solar desalination technologies. The present study examines the solar water desalination system with inclined steps, while considering various phase change materials (PCMs). The findings suggest that the incorporation of PCM generally enhances the productivity of the solar desalination system. Additionally, the combination of nanoparticles has been used to PCM, which is a popular technique utilized nowadays to improve the efficiency of these systems. The current investigation involves the transient modeling of a solar water desalination system, utilizing energy conservation equations. The equations were solved using the Runge–Kutta technique of the ODE23s order. The temperatures of the salt water, the absorbent plate of the glass cover, and the PCM were calculated at each time. Without a phase changer, the rate at which fresh water is produced is around 5.15 kg/m2·h. The corresponding mass flow rates of paraffin, n-PCM I, n-PCM III, n-PCM II, and stearic acid are 22.9, 28.9, 5.9, 11.9, and 73 kg/m2·h. PCMs, with the exception of stearic acid, exhibit similar energy efficiency up to an ambient temperature of around 29°. However, at temperatures over 29°, n-PCM II outperforms other PCM. HIGHLIGHTS The present study examines the solar water desalination system with inclined steps, while considering various phase change materials (PCMs).; The findings suggest that the incorporation of PCM generally enhances the productivity of the solar desalination system.;

Staphylococcus aureus is a bacterium responsible for resistance to multiple drugs and the efflux system is widely studied among the resistance mechanisms developed by this species. The present study evaluates the inhibition of the MepA efflux pump by thiadiazine-derived compounds. For this purpose, thiadiazine-derived compounds (IJ-14 to IJ-20) were tested against S. aureus K2068 strains. Microdilution tests were initially conducted to assess the Minimum Inhibitory Concentration (MIC) of the compounds and their efflux pump inhibition activity. In addition, fluorimetry tests were performed using BrEt emission and tests were conducted to inhibit the expression of the mepA gene. This involved comparing the bacterial gene expression with the antibiotic alone to the gene expression after combining compounds (IJ-17 and IJ-20) with the antibiotic. Furthermore, membrane permeability assessment tests and in silico molecular docking tests were performed. It was observed that the IJ17 and IJ20 compounds exhibited direct activity against the tested strain. The IJ17 compound produced significant results in the gene inhibition tests, which was also evidenced through the membrane permeability alteration test. These findings suggest that thiadiazine-derived compounds have promising effects against one of the main resistance mechanisms, with the IJ17 compound presenting observable mechanisms of action.

The major aim of the current study is to develop a data-driven methodology based on green processing for estimation of drug solubility in supercritical carbon dioxide as the solvent. Several machine learning algorithms were utilized to simulate Capecitabine solubility in supercritical carbon dioxide for green pharmaceutical manufacturing applications which can enhance the solubility of drugs by this method of processing. In the models, the inputs are pressure (P) and temperature (T), and the target output (Y) is solubility. Tree-based ensemble models of RF (Random Forest), ET (Extra Tree), and GB (Gradient Boosting) were selected for modeling in this research in combination with the optimizer to model the process. The hyper-parameters of models were optimized to reduce the error in the fitting. The coefficient of determination (R2 score) values obtained more than 0.96 and RMSE (root mean square error) for ET, GB, and RF models are 2.91, 2.37, and 4.45, respectively. Based on accurate analyses of results Gradient Boosting selected for primary model in this research. The models were able to estimate the drug solubility which can be used to estimate solubility for a wide range, thereby saving time and costs of measurements.

Continuous use of oral NSAIDs can damage mucosal membrane, which results in decreased bioavailability and non-compliance with the therapy. But the use of sustained release drug delivery systems might offer a solution. Objective was to synthesize mucoadhesive SR microspheres by using different combinations of pectin (PEC) and its thiolated derivative (T-PEC3100) for improved loxoprofen (LS) permeation. Thiolated pectin (T-PEC) was synthesized by the esterification method using thioglycolic acid. Thiolation was confirmed by thiol group quantification and charring point determination. Further characterization was done by Fourier Transform Infrared spectroscopy (FTIR), and Scanning electron microscopy (SEM). Ex-vivo mucoadhesion study was performed to confirm the improved characteristics. Microspheres (MS) were prepared using different ratios of PEC/T-PEC by solvent evaporation method and their particle size and surface morphology were evaluated. Mucus permeation study was carried out using the trans-well plate method. Sustained release behavior of prepared microspheres was investigated through the edema inhibition method in albino rats. T-PEC3100 was considered the optimum formulation for further evaluation and contained maximum thiol group content. FTIR spectra showed a characteristic peak of –SH and charring point was also changed considerably confirming the successful thiolation of PEC. SEM results showed spherical microspheres in the size range of 2–10 μm. Thiol-rich formulation of MS exhibited more than 80 % release after 12 h and maximum absorbable dose (MAD) was calculated as 400 μg % inhibition of edema in MS treated group was slowly attained initially but the reduction in inflammation was detected even after 24 h as compared to control group. Promising results from In-vivo edema inhibition study suggest the possible use of these thiolated MS in formulating sustained release formulation for arthritis.

This research work aimed to identify the main components that are responsible for the sedative properties of hop cones and allocate their targets. This investigation was performed through molecular docking, molecular dynamic simulations, root mean square fluctuation (RMSF) analysis, and DFT calculation techniques. The tested compounds from Humulus lupulus were compared to diazepam and paroxetine. Molecular docking showed that two-thirds of the compounds had a good affinity to gamma-aminobutyric acid (GABA), outperforming diazepam, while only three surpassed paroxetine on the SERT. Compounds 3,5-dihydroxy-4,6,6-tris(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (5) and (S,E)-8-(3,7-dimethylocta-2,6-dien-1-yl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one (15) showed stable binding and favorable energy parameters, indicating their potential for targeting GABA receptors and the SERT. This study provides a basis for future clinical research on these promising compounds.

Copaiba oil is widely used in medicine due to its antibacterial, anti-inflammatory, healing, antiviral, antiseptic and analgesic properties. Thus, the main objective of the study is to evaluate the antibacterial activity and modifier of the antibiotic action of the commercialized essential oil of four species of Copaifera spp. in combination with Ampicillin and LED lights against the multidrug-resistant strain of S. aureus (SA 10). The essential oil was obtained commercially through the dōTERRA® company. The evaluation of the antibacterial and modulating activity was performed using the microdilution methodology in a 96-well plate, using blue 415 nm, red 620 nm and yellow 590 nm LEDs and Ampicillin at an initial concentration of 1.024 µg/mL. The experiments were carried out in triplicate and submitted to ANOVA statistical analysis, considering a significant value of p

Artemisia nilagirica is an important medicinal plant found to exhibit several medicinal properties but the use of its leaves for combating E. coli infection has not been scientifically validated in poultry. The present study was conducted to evaluate the protective effects of methanol leaf extract of A. nilagirica (ANE) on E. coli challenged broiler chickens. Three hundred and thirty, day-old broiler chickens, were divided into 6 groups of 55 each, with group EX infected intraperitoneally (I/P) with LD50 dose of 1 × 107 cfu/ml of E. coli; group(s) EA1, EA2 and EA3 infected I/P with 1 × 107 cfu/ml of E. coli and supplemented with ANE @ 0.5, 1.0 and 2.0 g/L of drinking water, respectively; group AX were only given ANE @ 2.0 g/L in the drinking water. ANE treatment was started from day 4 and was continuously given in the drinking water up to day 21. E. coli infection was given to the birds on day 7 of their age. The effect of the plant extract was evaluated on the basis of gross, microscopic and ultrastructural alterations in E. coli challenged broiler chickens. The extract of A. nilagirica was found to show antibacterial, cardioprotective and hepatoprotective properties in a dose-dependent manner on the basis of gross and microscopic examination. The methanol extract of A. nilagirica leaves revealed no toxic effect on the hepatocytes on ultrastructural evaluation. This study demonstrates the antimicrobial, hepatoprotective and cardioprotective activities of ANE in broiler chickens infected with E. coli organism.

Cancer is one of the deadliest diseases to humanity. There is significant progress in treating this disease, but developing some drugs that can fight this disease remains a challenge in the field of medical research. Thirteen new 1,2,3-triazole linked tetrahydrocurcumin derivatives were synthesized by click reaction, including a 1,3-dipolar cycloaddition reaction of tetrahydrocurcumin baring mono-alkyne with azides in good yields, and their in vitro anticancer activity against four cancer cell lines, including human cervical carcinoma (HeLa), human lung adenocarcinoma (A549), human hepatoma carcinoma (HepG2), and human colon carcinoma (HCT-116) were investigated using MTT(3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetraz-olium bromide) assay. The newly synthesized compounds had their structures identified using NMR HRMS and IR techniques. Some of prepared compounds, including compounds 4g and 4k, showed potent cytotoxic activity against four cancer cell lines compared to the positive control of cisplatin and tetrahydrocurcumin. Compound 4g exhibited anticancer activity with a IC50 value of 1.09 ± 0.17 μM against human colon carcinoma HCT-116 and 45.16 ± 0.92 μM against A549 cell lines compared to the positive controls of tetrahydrocurcumin and cisplatin. Moreover, further biological examination in HCT-116 cells showed that compound 4g can arrest the cell cycle at the G1 phase. A docking study revealed that the potential mechanism by which 4g exerts its anti-colon cancer effect may be through inhabiting the binding of APC–Asef. Compound 4g can be used as a promising lead for further exploration of potential anticancer agents.

Abstract Researchers are constantly searching for drugs to combat the coronavirus pandemic caused by SARS-CoV-2, which has lasted for over two years. Natural compounds such as phenolic acids are being tested against Mpro and AAK1, which are key players in the SARS-CoV-2 life cycle. This research work aims to study the ability of a panel of natural phenolic acids to inhibit the virus's multiplication directly through Mpro and indirectly by affecting the adaptor-associated protein kinase-1 (AAK1). Pharmacophore mapping, molecular docking, and dynamic studies were conducted over 50 ns and 100 ns on a panel of 39 natural phenolic acids. Rosmarinic acid (16) on the Mpro receptor (− 16.33 kcal/mol) and tannic acid (17) on the AAK1 receptor (− 17.15 kcal/mol) exhibited the best docking energy against both receptors. These favourable docking score values were found to be superior to those of the co-crystallized ligands. Preclinical and clinical research is required before using them simultaneously to halt the COVID-19 life cycle in a synergistic manner.

Industrial application of novel, green and effective liquid absorbents for improving the separation yield of CO2 greenhouse pollutant is an important milestone to reduce its emission to the atmosphere. In this research, the separation performance of three novel and green ionic liquids (ILs) including [bmim][PF6], [bmim][BF4] and [emim][etSO4] are compared with pure water to evaluate the feasibility of their employment to enhance the removal potency of CO2 through the membrane contactor. With the aim of reaching this goal, a finite element-based model and a numerical simulation are developed to solve the momentum/mass transfer equations and predict the results. Based on the modeling/simulation outcomes, the addition of the abovementioned ILs could substantially increase the separation of CO2 molecules compared to pure water. Based on the results, [bmim][BF4] is introduced as the most efficient IL with the separation efficiency of 100 % (100 % [bmim][BF4]> 99 % [bmim][PF6]> 97.5 % [emim][etSO4]> 55 % pure water). Furthermore, the effects of different operational/functional parameters (i.e., gas flow rate, porosity, fibers’ number and packing density) on the CO2 separation efficacy is comprehensively discussed.

The present study utilized molecular docking and density functional theory (DFT) approaches, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties to investigate the binding interactions, reactivity, stability, and drug-likeness of curcumin (1), tetrahydrocurcumin (2), and tetrahydrocurcumin derivatives (3–6) as potential anti-cancer agents. MGL (Molecular Graphic Laboratory) and Discovery Studio Visualizer (DSV) software employed for docking studies. Pharmacokinetic and pharmacodynamic (ADME-Tox) analyses were conducted using SwissADME and pKCSM web servers. Total Electron Density (TED) measurements identified molecular adsorption sites, considering various factors, including quantum chemical characteristics, to assess compound effectiveness using DFT method implanted in the Gaussian software. The binding energy (Eb) from docking simulations was used to evaluate inhibitory potential. ADMET analysis suggested favorable oral bioavailability and pharmacokinetics for all studied substances, excluding compound 4. DFT and docking investigations highlighted compounds 1, 2, and 6 as optimal scaffolds for drug design based on in silico screening tests.

Ethnopharmacological relevance: Therapeutic botanicals (plants and derivatives) are in use since antiquity for various health ailments. The ethnic community is the repository of the information, the multifactorial therapeutic applications of which may often need scientific validation. The spreading hogweed or Boerhaavia diffusa L., also known as Punarnava, is a reassuring medicinal herb with diverse pharmacological benefits. It is used in Ayurveda in Asia and Africa as a rejuvenator or “Rasayan” for its excellent antiaging and antioxidant properties.Aim: The study aimed at compiling the state-of-art knowledge of the medicinal benefits of Boerhaavia diffusa L. and unraveling the unexplored commercially useful bioactive constituents by establishing their possible pharmacological benefits.Methods: The data from published literature, confined to pharmacological manifestations of various phytocomponents of Boerhaavia diffusa L. or its parts like root, leaf and stem were extracted from scientific databases, Google, Science Direct, PubMed, etc. using its antifungal, antibacterial, anticancer, anti-inflammatory, antidiabetic, hepatoprotective, cardioprotective, renoprotective, antifertility benefits and molecular docking study as search strings and keywords. Further, the reported in silico studies for bioactivity and bioavailability are detailed.Results: The botanicals possess numerous bioactive compounds, the most widely reported ones being phenolic (punarnavoside, trans-caftaric acid, boerhavic acid), rotenoid (boeravinones A-J), flavonoid (borhaavone, quercetin, kaempferol), isoflavonoid (2′-O-methyl abronisoflavone), alkaloid (punarnavine), steroid (boerhavisterol, β-Ecdysone), anthracenes and lignans (liriodendrin, syringaresinol mono-β-D-glucoside). Some of the reported reassuring benefits of their purified forms or even the crude extracts are antidiabetic, antimicrobial, anticancer, antioxidant, anti-inflammatory, hepatoprotective, renoprotective, cardioprotective, antifertility, etc.Conclusion: The article provides an extensive study on such pharmacological utility to support the ethnomedicinal use of Boerhaavia diffusa L. and propose possible mechanism of the various bioactive compounds in optimising metabolic dysfunctions, healing and protecting vital body organs, often related to the magnificent antioxidant property of this ayurvedic panacea. Further, establishing specific roles of its yet-to-explore bioactive constituents for diverse pharmacological applications is suggested.

Stable angina (angina pectoris) is a type of chest pain that happens when the heart muscle needs more oxygen than usual but it's not getting it at that moment because of heart disease. The drawback of the marketed formulation is required repeated administration of the drug due to low bioavailability. A recently licenced medication called ivabradine hydrochloride (IVB) is used to treat stable angina and signs of heart failure. Technical problems in the approved IBH tablets include a two-hour half-life, erratic systemic absorption, and a high rate of first-pass metabolism (>50%). We therefore created a distinctive and cutting-edge formulation of IVB using a nano formulation approach like nanostructured lipid carriers (NLCs). The response surface method with a three-level Box–Behnken design was used for the creation and improvement of IVB. The optimized formulation was proceeded for physicochemical characterizations like particle size, zeta potential, morphology (TEM and SEM), entrapment efficiency, in-vitro release, stability studies, compatibility study (DSC, FTIR and XRD), hemocompatibility study, ex-vivo permeability, and in-vivo angina study. As results, optimized formulation was found to be 114.45 ± 5.14 nm particle size with 83.45 ± 3.23% entrapment efficiency and biphasic release. The formulation showed spherical and compatible with excipients, no interaction was observed and hemocompatible. The IBH-NLCss showed more permeability (1.85 folds) as compared to the marketed dosage form. The in-vivo pharmacological activity was established in terms of decrease in severity and duration of ST-segment depression in vasopressin-induced angina model in experimental rats.

Determination of drug solubility in supercritical solvents such as CO2 has been of great importance for preparation of nanomedicines. This study implements and tunes several machine learning models to describe the solubility of medicine and density of solvent at various pressure and temperature. The dataset used in this study consisted of the input variables, temperature, and pressure. The methods of AdaBoost algorithm to boost the performance of base regression models for predicting the mole fractions of rivaroxaban and the density of SC-CO2 were developed. The base models used include Theil-Sen Regression (TSR), Gaussian Process Regression (GPR), Automatic Relevance Determination Regression (ARD), and Linear Regression (LR). We employ the Hunter-Prey Optimization technique to tune the hyper-parameters of these models. The results indicated that the boosted models outperform their base counterparts. For the mole fraction predictions, AdaBoost with ARD achieves an R2 value of 0.95986, while AdaBoost with GPR obtains an R2 score of 0.99817. For the SC-CO2 density predictions, AdaBoost with GPR achieves an impressive R2 of 0.99906. Accordingly, the AdaBoost with GPR is the best model for both outputs. These results demonstrate AdaBoost strength and Hunter-Prey algorithm in enhancing the predictive accuracy of regression models for these chemical properties.

This study presents a comparative analysis of three different models, namely Deep Neural Network (DNN), Quantile Regression (QR), and K-Nearest Neighbors (KNN) for the prediction of SC-CO2 density and solubility of rivaroxaban. The models were tuned using the Fireworks Algorithm (FWA) to optimize their hyperparameters. The dataset used in this analysis consisted of temperature (T), pressure (P), SC-CO2 density, and mole fractions of rivaroxaban. The results indicate that the DNN model exhibited outstanding performance in both prediction tasks. For the prediction of SC-CO2 density, the DNN model achieved an impressive R2 score of 0.99667, with a mean absolute error (MAE) of 7.61812E+00. Similarly, for the prediction of mole fractions of rivaroxaban, the DNN model achieved an excellent R2 score of 0.99831, with a very low MAE of 2.49870E-02. The KNN model also demonstrated good performance, with R2 scores of 0.9799 and 0.98029 for SC-CO2 density and mole fractions, respectively. However, it exhibited slightly higher MAE values compared to the DNN model. On the other hand, the QR model showed relatively lower accuracy in both prediction tasks, with R2 scores of 0.90873 and 0.87362 for SC-CO2 density and mole fractions, respectively. The QR model had higher MAE values, indicating larger average deviations from the true values. Overall, the DNN model outperformed both the KNN and QR models in predicting SC-CO2 density and mole fractions of rivaroxaban. These findings highlight the effectiveness of DNN models in accurately modeling and predicting complex chemical properties.

Preparation of small-molecule API (Active Pharmaceutical Ingredient) at submicron size would be of great benefit for pharmaceutical engineering, as the drug particles at submicron size possess higher solubility in water. Indeed, the drug bioavailability can be enhanced when the nanomedicine is prepared. In this study, the solubility of the drug desoxycorticosterone acetate (DA) is being examined to assess its viability of nanonization using supercritical operation. Two inputs are temperature and pressure which were considered for machine learning modeling in this study. The drug's solubility is the only output to be estimated by the optimized models. This dataset has 45 rows of data that were gathered at 5 different pressure and temperature levels. Support vector machine (SVM) is used as the core of the models built in this research. Epsilon-SVR and nu-SVR are models based on this concept, which together with two different polynomial and RBF kernels form the four models built in this research for estimation of DA drug solubility. The models are also optimized with the help of a new TLCO method. All four final models have an R2 score higher than 0.9, and among them, the Epsilon-SVR model with RBF kernel has the best performance with 0.967.

Background/purpose: Chlorothiazide is a well-known diuretic and an antihypertensive drug with poor solubility and permeability and thus low bioavailability. Producing nanoparticles of this drug via a suitable supercritical method can enhance its therapeutic efficiency. For this purpose, supercritical solubility of Chlorothiazide must be known. At 308- 338 K and 130- 290 bar, Majrashi obtained this parameter between the mole fraction of 0.417×10-5 to 1.012×10-5. The poor supercritical solubility of Chlorothiazide can be enhanced by adding a little polar co-solvent to scCO2. Model/design: In the current study, the solubility of this drug in the ternary systems of Chlorothiazide, scCO2, and different co-solvents of ethanol, DMSO, and acetone was measured. Also, the obtained experimental data were correlated by some empirical models presented by the research teams of González, Mendez-Santiago-Teja, Li, Soltani-Mazloumi, and Jouyban. Finding: The supercritical solubility of Chlorothiazide in the presence of ethanol, DMSO, and acetone was found in the mole fraction range of 1.115×10-5 to 11.895×10-5, 0.778×10-5 to 9.25×10-5, and 0.668 ×10-5 to 9.04×10-5, respectively. It has been shown that addition of these co-solvents can improve the supercritical solubility of Chlorothiazide, and in the meantime, ethanol with the greatest effect can increase it by about 2.02-11.75 times. Furthermore, the Joyban model has the most accuracy for the correlation of the obtained solubility data, and the data calculated by this model are more consistent with the experimental data. Novelty: For the first time at this work, the effect of three different co-solvents of ethanol, DMSO, and acetone on the solubility of Chlorothiazide in scCO2 was studied both experimentally and theoretically.

Modeling and simulations based on machine learning techniques were conducted in this research for determination of pharmaceutical solubility in supercritical solvent for the sake of green processing development in the area of pharmaceutics. By this method, drug nanoparticles can be formed and controlled for better solubility and consequently bioavailability. We modeled the solubility of the drug namely desoxycorticosterone acetate (DA). The temperature and pressure are two inputs for the developed models, whereas the target output is the solubility of DA in the solvent. Indeed, models with two inputs and one output are developed in this study. This dataset contains 45 rows of data collected at five distinct temperatures and nine pressure levels. Three novel models are employed here including: HHO-MLP, HHO-RR, and HHO–KNN for theoretical determination of the drug solubility in the solvent. They are in fact MLP, Ridge Regression, and KNN models coupled with Harris Hawks optimizer (HHO) for hyper-parameter optimization. The HHO-MLP model has the best performance among models with R2 of 0.995, RMSE error rate of 0.194 and maximum error equal to 0.327. The model's findings can be used for estimation of the solubility data in wide range of T and P.

The present work described the synthetic procedure adopted for the synthesis of bis-indole-based triazine derivatives via a series of reactions. All the compounds were synthesized through a stepwise reaction. After being confirmation through thin-layer chromatography (TLC) these compounds were characterized through various spectroscopic techniques including 1HNMR, 13CNMR and HREI-MS and evaluated against beta-glucuronidase in the presence of standard drug D-saccharic acid 1,4 lactone (IC50 = 31.2 ± 1.0 µM). Most of the synthesized derivatives were found with better to good inhibitory potentials (IC50 = 5.30 ± 2.0 µM to 33.10 ± 1.0 µM). SAR explains better results of analogs due to the presence of varied substituents on the aromatic rings. In this regard, the excellent potential was shown by analogs 1, 3, 6, 8 and 9 with IC50 = 5.30 ± 2.0, 7.10 ± 4.0, 6.10 ± 3.0, 8.40 ± 1.0 and 7.20 ± 3.0 µM respectively). In addition, all the synthesized analogs were evaluated for anti-cancer and anti-bacterial (E. coli) activities in which the targeted compounds were found with significant potentials in the presence of standard drugs Tetrandrineb (IC50 = 1.37 ± 0.10 µM) and streptomycin respectively. These derivatives were further subjected to molecular docking studies in order to investigate better binding sites with distance. Additionally, ADME properties for the synthesized compounds were also explored the drug like properties of the synthesized compounds.

This study aim to synthesize new 1,3,4-oxadiazole derivatives incorporating mefenamic acid as promising α-glucosidase and urease inhibitors, potentially leading to the treatment of postprandial hyperglycemia as well as H. pylori related disorders. In this regards, we have designed a series of Mefenamic acid derivatives. The synthetic compounds were structurally elucidated through 1H NMR, 13C NMR and HR-EIMS analysis. The biological evaluation of these derivatives against α-glucosidase and urease enzyme depicted some novel derivatives with potent inhibition against the said enzymes. All the derivatives exhibited potent inhibition against α-glucosidase enzymes with IC50 ranging from 25.81 ± 1.63–113.61 ± 1.31 µM against standard drug acarbose (IC50 = 375.82 ± 1.76 µM) while with respect to urease these derivatives possessed inhibitory potential varied between IC50 = 8.04 ± 1.01–58.18 ± 1.03 µM against the standard thiourea (IC50 = 21.0 ± 1.76 µM). The cell viability results revealed that all of the derivatives were found least cytotoxic. Furthermore, molecular docking studies of the most potent derivatives identify number of key features involved in binding interactions between potential inhibitors and the enzyme's active site.

Production of solid-dosage drug nanoparticles was assessed by theoretical models to investigate the possibility of drug treatment via supercritical green processing. Nanonization can enhance drug solubility and consequently its bioavailability which is of great importance for pharmaceutical industry. This research presents a comparative study of three different regression models including Gaussian process regression, k-nearest neighbors, and multi-layer perceptron for predicting solvent density and solubility of Hyoscine drug. The models optimized using political optimizer (PO) algorithm. The results showed that all three optimized methods were able to predict density and solubility with high accuracy. PO-GPR achieved the highest R2 score for solubility (0.9984) and same for density (0.9999). The PO-MLP model achieved the high R2 score for density (0.9997) and the second-highest score for solubility (0.9945). PO-KNN also showed good performance for density (R2 = 0.9557) and solubility (R2 = 0.9783) but was outperformed by the other two models. In terms of RMSE and AARD%, PO-GPR and PO-MLP achieved lower error rates compared to PO-KNN. Overall, the results suggest that PO-GPR and PO-MLP are promising methods for predicting density and solubility of values. The models were useful for the application of drug nanonization and can be used to optimize the process.

The method of green technology which is based on supercritical solvent has been studied in this work for analysis of nanomedicine preparation of solid dosage oral medications. Given that the poor drug solubility in aqueous media is a big challenge in pharmaceutical industry, nanomedicines would help improve the drug solubility in aqueous media. The solubility of fludrocortisone acetate in supercritical carbon dioxide is modelled in this research using various machine learning methods because it is a crucial aspect of the expansion of the pharmaceutical business. For this purpose, the accessible data have two input features: a pressure range of 120–300 (bar) and a temperature range of 308–338 (K). MLP, v-SVR and MLR are the basic models used in this research, but not their raw versions. They are improved for modeling drug solubility and coupled with the grey wolf optimization (GWO) in order to optimize the models. The models optimized by GWO showed acceptable results, but among these models, MLP regression has shown better results when coupled with this optimization algorithm. This model has the RMSE error rate of 2.98 × 10−2 and its R2 score is 0.9797 in correlating the solubility data of the medicine.

Abstract Background Exposure to cadmium is implicated in the etiology of some neurodegenerative diseases. Compounds isolated from Ipomoea cairica extract are neuroprotective. However, there is no reported neuroprotective activity of the crude extract of I. cairica (ICE). We investigated the neuroprotective activity of I. cairica extract against cadmium-induced biochemical changes in the brain of male Wistar rats. Thirty-six animals were divided into four groups of 9 animals per group: group I (Control); group II (3.5 mg/kg CdCl2); group III (100 mg/kg ICE + CdCl2); and group IV (250 mg/kg ICE + CdCl2). Animals were pretreated with 100 and 250 mg/kg ICE before co-administration with cadmium chloride. Results CdCl2 treatment caused a significant increase in acetylcholineesterase activity, lipid peroxidation, beta-amyloid aggregation, caspase 3 and 9, p53, and glutamate concentration. In addition, CdCl2 caused a significant decrease in catalase activity, superoxide dismutase, glutathione-S-transferase, Na+/K+ ATPase, and glutamate dehydrogenase. ICE was able to reduce the neuronal damaging effect of CdCl2 by acting as an antioxidant, antiapoptotic, anticholinesterase, and antiexcitotoxicity. Conclusions Our findings show that Ipomoea cairica leaf can be developed and included in the natural product in the prevention of neurodegenerative diseases.

In continuation of our research programs for the discovery, production, and development of the pharmacological activities of molecules for various disease treatments, Schiff bases and pyrazole scaffold have a broad spectrum of activities in biological applications. In this context, this manuscript aims to evaluate and study Schiff base–pyrazole molecules as a new class of antioxidant (total antioxidant capacity, iron-reducing power, scavenging activity against DPPH, and ABTS radicals), anti-diabetic (α-amylase% inhibition), anti-Alzheimer’s (acetylcholinesterase% inhibition), and anti-arthritic (protein denaturation% and proteinase enzyme% inhibitions) therapeutics. Therefore, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were designed and synthesized for evaluation of their antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic properties. The results for compound 22b demonstrated significant antioxidant, anti-diabetic (α-amylase% inhibition), and anti-Alzheimer’s (ACE%) activities, while compound 23a demonstrated significant anti-arthritic activity. Prediction of in silico bioinformatics analysis (physicochemical properties, bioavailability radar, drug-likeness, and medicinal chemistry) of the target derivatives (22a, b and 23a, b) was performed. The molecular lipophilicity potential (MLP) of the derivatives 22a, b and 23a, b was measured to determine which parts of the surface are hydrophobic and which are hydrophilic. In addition, the molecular polar surface area (PSA) was measured to determine the polar surface area and the non-polar surface area of the derivatives 22a, b and 23a, b. This study could be useful to help pharmaceutical researchers discover a new series of potent agents that may act as an antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic.

Depression is the major mental illness which causes along with loss of interest in daily life, a feeling of hopelessness, appetite or weight changes, anger and irritability. Due to the hepatic first-pass metabolism, the absolute bioavailability of fluvoxamine (FVM) after oral administration is about 50%. By avoiding the pre-systemic metabolism, nasal delivery would boost bioavailability of FVM. Additionally, the absorption is anticipated to occur more quickly than it would via the oral route because of the existence of microvilli and high vasculature. A nonionic surfactant, cholesterol and an arachidonic acid-carboxymethyl chitosan (AA-CMCS) conjugate were used to develop FVM-loaded novasomes. To investigate the effects of surfactant concentration, AA-CMCS conjugate concentration and stirring speed on the novasomes’ characteristics, a Box–Behnken design was used. The dependent variables chosen were zeta potential, polydispersity index and particle size. The AA-CMCS conjugate was confirmed by 1H-NMR and FTIR. Using Design Expert software (version 7; Stat-Ease Inc., Minneapolis, MN, USA), novasomes were further optimized. The chosen optimal formulation (NAC8) was made up of AA-CMCS conjugate, Span 60 and cholesterol. Particle size, zeta potential and PDI values for NAC8 formulation were 101 nm, −35 mV and 0.263, respectively. The NAC8 formulation’s DSC and TGA analysis demonstrated that the medication had been uniformly and amorphously distributed throughout the novasomes. The NAC8 formulation showed 99% and 90% FVM release and permeation, respectively, and the novasome adherence time was 24 h. An improved antidepressant effect along with five-fold increase in bioavailability of FVM was observed after trans-nasal administration of NAC8 formulation compared to the reference commercially available Flumin® tablets. FVM-loaded novasomes administered via the nasal route may therefore constitute an advancement in the management of depression.

Abstract Pseudomonas aeruginosa is an opportunistic bacterium causing several health problems and having many virulence factors like biofilm formation on different surfaces. There is a significant need to develop new antimicrobials due to the spreading resistance to the commonly used antibiotics, partly attributed to biofilm formation. Consequently, this study aimed to investigate the anti-biofilm and anti-quorum sensing activities of Dioon spinulosum, Dyer Ex Eichler extract (DSE), against Pseudomonas aeruginosa clinical isolates. DSE exhibited a reduction in the biofilm formation by P. aeruginosa isolates both in vitro and in vivo rat models. It also resulted in a decrease in cell surface hydrophobicity and exopolysaccharide quantity of P. aeruginosa isolates. Both bright field and scanning electron microscopes provided evidence for the inhibiting ability of DSE on biofilm formation. Moreover, it reduced violacein production by Chromobacterium violaceum (ATCC 12,472). It decreased the relative expression of 4 quorum sensing genes (lasI, lasR, rhlI, rhlR) and the biofilm gene (ndvB) using qRT-PCR. Furthermore, DSE presented a cytotoxic activity with IC50 of 4.36 ± 0.52 µg/ml against human skin fibroblast cell lines. For the first time, this study reports that DSE is a promising resource of anti-biofilm and anti-quorum sensing agents.

To discover anti-acetylcholinesterase agents for the treatment of Alzheimer’s disease (AD), a series of novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), and High-Resolution Mass Spectrometry (HRMS) analyses. These hybrids were evaluated for their potential inhibitory effect on acetylcholinesterase (AChE). All of them exhibited excellent inhibitory activity against AChE. The IC50 values ranged from 87.84 to 515.59 μg/mL; hybrids 13c and 13d with IC50 values of 0.232 ± 0.011 and 0.190 ± 0.004 µM, respectively, showed the most potent activity as acetylcholinesterase inhibitors (AChEIs). The reference drug, Galantamine, yielded an IC50 of 1.142 ± 0.027 µM. Reactivity descriptors, including chemical potential (μ), chemical hardness (η), electrophilicity (ω), condensed Fukui function, and dual descriptors are calculated at wB97XD/6-311++ G (d,p) to identify reactivity changes of the designed compounds. An in-depth investigation of the natural charge pattern of the studied compounds led to a deep understanding of the important interaction centers between these compounds and the biological receptors of AChE. The molecular electrostatic surface potential (MESP) of the most active site in these derivatives was determined using high-quality information and visualization. Molecular docking analysis was performed to predict binding sites and binding energies. The structure-activity-property relationship studies indicated that the proposed compounds exhibit good oral bioavailability properties. To explore the stability and dynamic behavior of the ligand-receptor complexes, molecular dynamics simulations (MDS) were performed for 100 ns on the two best docked derivatives, 13c and 13d, with the AChE (4EY7) receptor. A popular method for determining the free binding energies (MM/GBSA) is performed using snapshots taken from the systems’ trajectories at 100 ns. These results revealed that the complex system of compound 13d acquired a relatively more stable conformation and exhibited better descriptors than the complex system of compound 13c and the Galantamine drug, suggesting its potential as an effective inhibiting drug. The binding free energy analysis revealed that the 13d-4EY7 complex exhibited greater stability with AChE receptors compared to other complexes.

Glaucoma is a progressive optic neuropathy characterized by a rise in the intraocular pressure (IOP) leading to optic nerve damage. Bimatoprost is a prostaglandin analogue used to reduce the elevated IOP in patients with glaucoma. The currently available dosage forms for Bimatoprost suffer from relatively low ocular bioavailability. The objective of this study was to fabricate and optimize solid lipid nanoparticles (SLNs) containing Bimatoprost for ocular administration for the management of glaucoma. Bimatoprost-loaded SLNs were fabricated by solvent evaporation/ultrasonication technique. Glyceryl Monostearate (GMS) was adopted as solid lipid and poloxamer 407 as surfactant. Optimization of SLNs was conducted by central composite design. The optimized formulation was assessed for average particle size, entrapment efficiency (%), zeta potential, surface morphology, drug release study, sterility test, isotonicity test, Hen’s egg test-chorioallantoic membrane (HET-CAM) test and histopathology studies. The optimized Bimatoprost-loaded SLNs formulation had an average size of 183.3 ± 13.3 nm, zeta potential of −9.96 ± 1.2 mV, and encapsulation efficiency percentage of 71.8 ± 1.1%. Transmission electron microscopy (TEM) study revealed the nearly smooth surface of formulated particles with a nano-scale size range. In addition, SLNs significantly sustained Bimatoprost release for up to 12 h, compared to free drug (p < 005). Most importantly, HET-CAM test nullified the irritancy of the formulation was verified its tolerability upon ocular use, as manifested by a significant reduction in mean irritation score, compared to positive control (1% sodium dodecyl sulfate; p < 0.001). Histopathology study inferred the absence of any signs of cornea tissue damage upon treatment with Bimatoprost optimized formulation. Collectively, it was concluded that SLNs might represent a viable vehicle for enhancing the corneal permeation and ocular bioavailability of Bimatoprost for the management of glaucoma.

Periodontitis is an inflammatory disorder associated with dysbiosis and characterized by microbiologically related, host-mediated inflammation that leads to the damage of periodontal tissues including gingiva, connective tissues, and alveolar bone. The aim of this study was to develop an in situ gel consisting of piperine. Eight in situ gel formulations were designed by varying the concentration of deacylated gellan gum cross-linked with sodium tripolyphosphate, and poloxamer-407. The prepared gels were evaluated for gelation temperature, gelation time, viscosity, piperine-loading efficiency, and piperine release. Finally, the optimized formula was evaluated for anti-inflammatory effectiveness among human patients during a 14-day follow-up. The optimized in situ gel formulation exhibited a gelation temperature of 35 ± 1 °C, gelling of 36 ± 1 s, excellent syringeability, and piperine loading of 95.3 ± 2.3%. This formulation efficiently sustained in vitro drug release for up to 72 h. In vivo studies revealed an efficient sol-to-gel transformation of optimized in situ gel formulation at physiological conditions, permitting an efficient residence time of the formulation within a periodontitis pocket. Most importantly, a clinical study revealed that treatment with the optimized formulation elicited a significant reduction in the mean plaque score (p = 0.001), gingival index (p = 0.003), and pocket depth (p = 0.002), and exerted a potent anti-inflammatory potential, compared to the control group. Collectively, piperine-loaded in situ gel might represent a viable therapeutic approach for the management of gingival and periodontal diseases.

The particle size at the nanometric level allows the manifestation of remarkable properties, chiefly due to changes in surface-to-volume ratio. This study is attributed to the novel green synthesis of nano silver by using essential oils as a capping and reducing agent. Clove oil, cinnamon oil, and cardamom oil were selected for the eco-friendly and low-cost fabrication of silver nanoparticles. The prepared nanoparticles were characterized by photoluminescence spectroscopy, FT-IR spectroscopy, X-Ray diffraction, energy dispersive X-ray spectroscopy, dynamic laser light scattering, thermogravimetric analysis, and transmission electron microscopy. It was found that samples prepared by using cinnamon oil (20 nm) and cardamom oil (12 nm) had smaller particle sizes as compared to those synthesized by using clove oil (45 nm). All the prepared samples exhibited very strong antimicrobial activities with a clear zone of inhibition (6–24 mm) against Staphylococcus aureus, Klebsiella pneumoniae, and Candida albicans. Very resilient photocatalytic activities of the samples were observed against Allura red and fast green dyes. It was concluded that the cinnamon oil-based system is the best size reducer and size homogenizer (less chances of agglomeration) as compared to clove oil and cardamom oil (more chances of agglomeration) for the synthesis of silver nanoparticles.

This study demonstrates high drug-loading of novel pyridine derivatives (S1–S4) in lipid- and polymer-based core–shell nanocapsules (LPNCs) for boosting the anticancer efficiency and alleviating toxicity of these novel pyridine derivatives. The nanocapsules were fabricated using a nanoprecipitation technique and characterized for particle size, surface morphology, and entrapment efficiency. The prepared nanocapsules exhibited a particle size ranging from 185.0 ± 17.4 to 223.0 ± 15.3 nm and a drug entrapment of >90%. The microscopic evaluation demonstrated spherical-shaped nanocapsules with distinct core–shell structures. The in vitro release study depicted a biphasic and sustained release pattern of test compounds from the nanocapsules. In addition, it was obvious from the cytotoxicity studies that the nanocapsules showed superior cytotoxicity against both MCF-7 and A549 cancer cell lines, as manifested by a significant decrease in the IC50 value compared to free test compounds. The in vivo antitumor efficacy of the optimized nanocapsule formulation (S4-loaded LPNCs) was investigated in an Ehrlich ascites carcinoma (EAC) solid tumor-bearing mice model. Interestingly, the entrapment of the test compound (S4) within LPNCs remarkably triggered superior tumor growth inhibition when compared with either free S4 or the standard anticancer drug 5-fluorouracil. Such enhanced in vivo antitumor activity was accompanied by a remarkable increase in animal life span. Furthermore, the S4-loaded LPNC formulation was tolerated well by treated animals, as evidenced by the absence of any signs of acute toxicity or alterations in biochemical markers of liver and kidney functions. Collectively, our findings clearly underscore the therapeutic potential of S4-loaded LPNCs over free S4 in conquering EAC solid tumors, presumably via granting efficient delivery of adequate concentrations of the entrapped drug to the target site.

The emergence of several novel SARS-CoV-2 variants regarded as variants of concern (VOCs) has exacerbated pathogenic and immunologic prominences, as well as reduced diagnostic sensitivity due to phenotype modification-capable mutations. Furthermore, latent and more virulent strains that have arisen as a result of unique mutations with increased evolutionary potential represent a threat to vaccine effectiveness in terms of incoming and existing variants. As a result, resisting natural immunity, which leads to higher reinfection rates, and avoiding vaccination-induced immunization, which leads to a lack of vaccine effectiveness, has become a crucial problem for public health around the world. This study attempts to review the genomic variation and pandemic impact of emerging variations of concern based on clinical characteristics management and immunization effectiveness. The goal of this study is to gain a better understanding of the link between genome level polymorphism, clinical symptom manifestation, and current vaccination in the instance of VOCs.

Eight polymer-metal complexes were synthesized from complexation of divalent Mn(II), Ni(II), Co(II), and Cu(II) metal ions with modified polystyrene-alt-(maleic anhydride) (PSMAP and PSMAM) ligands. The structures of these new complexes were characterized using a variety of techniques, including magnetic moment susceptibility, conductance measurements, FT-IR spectroscopy, ultraviolet-visible (UV-VIS), thermogravimetric analysis (TGA), as well as scanning electron microscopy (SEM). All metal-polymer complexes have a non-electrolytic nature based on conductance measurements. The polymer molecule behaves as neutral bidentate NO ligand through O atoms of carbonyl (C=O) and N atoms of amide (O=C-NH). Divalent Mn2+, Ni2+, Co2+ and Cu2+ complexes have an octahedral geometry based on their electronic spectra and magnetic values. Based on thermal analysis data, those new complexes are more thermally stable than the ligands. SEM and TEM are manipulated to give the surface structure and the particle size measurements where they give different shapes and sizes of the synthesized complexes.

Tea is the third most consumed beverage in Saudi Arabia (a country in the Middle East) after water and Arabian coffee. Hence, a large amount of consumed tea leaves is discarded as solid waste. Waste tea leaves (WTLs) have no commercial value and could be considered as an environmentally sustainable costless material. This work aimed to manufacture an adsorbent material from the discarded WTLs and charge-transfer (CT) interaction and use this adsorbent material effectively for the removal of different kinds of pollutants from water. The adsorbent material was manufactured in three steps. First, a CrFeO3 metal composite was synthesized from the CT interaction between FeCl3 and CrCl3 with urea. Second, activated carbons were prepared from consumed WTLs using facile and clean treatments of pre-carbonization, and a simple potassium hydroxide (KOH) activation treatment. Finally, the adsorbent material was fabricated by grounding CrFeO3 composite with the activated carbons in a 1:10 molar ratio (metal composite to activated carbons). The prepared materials were characterized spectroscopically and morphologically using FT-IR, XRD, SEM/EDX, and TEM analysis. The synthesized absorbent material was used to adsorb two organic dyes (Azocarmine G2; M1, and Methyl violet 2B; M2), and two commercial pesticides (Tiller 480SL; M3, and Acochem 25% WP; M4) from aqueous solution, and it showed promising adsorption efficacy. The minimum adsorbent material’s dosage to obtain a maximum removal efficiency (R%) for M1, M2, M3, and M4 removal from 100 mL solution (100 mg/L) was 0.11, 0.14, 0.13, and 0.12 g, respectively. The max R% for M1 (96.8%) was achieved in the first 45 min, the max R% for M2, 95.5%, was achieved during the first 55 min, and the max R% for M3 (96.4%) was achieved in the first 35 min, while the max R% for M4, 98.6%, was achieved during the first 35 min.

Development in the fields of natural-product-derived and synthetic small molecules is in stark contrast to the ongoing demand for novel antimicrobials to treat life-threatening infections caused by extended-spectrum β-lactamase producing Escherichia coli (ESBL E. coli). Therefore, there is an interest in the antibacterial activities of synthesized N-(4-methylpyridin-2-yl) thiophene-2-carboxamides (4a–h) against ESBL-producing E. coli ST131 strains. A blood sample was obtained from a suspected septicemia patient and processed in the Bactec Alert system. The isolate’s identification and antibacterial profile were determined using the VITEK 2® compact system. Multi-locus sequence typing of E. coli was conducted by identifying housekeeping genes, while ESBL phenotype detection was performed according to CLSI guidelines. Additionally, PCR was carried out to detect the blaCTX-M gene molecularly. Moreover, molecular docking studies of synthesized compounds (4a–h) demonstrated the binding pocket residues involved in the active site of the β-lactamase receptor of E. coli. The result confirmed the detection of E. coli ST131 from septicemia patients. The isolates were identified as ESBL producers carrying the blaCTX-M gene, which provided resistance against cephalosporins and beta-lactam inhibitors but sensitivity to carbapenems. Among the compounds tested, 4a and 4c exhibited high activity and demonstrated the best fit and interactions with the binding pocket of the β-lactamase enzyme. Interestingly, the maximum of the docking confirmations binds at a similar pocket region, further strengthening the importance of binding residues. Hence, the in vitro and molecular docking studies reflect the promising antibacterial effects of 4a and 4c compounds.

Three new transition-metal complexes were produced by refluxing azodicarbonamide (ADCA) with nickel(II), copper(II), and zinc(II) solutions in a mixture of 50% (v/v) methanol and water. The magnitude of chelation between metal ions and ligand molecules was assessed by FT-IR, UV, elemental analysis, TGA, conductivity, mass, and magnetic susceptibility measurements. FT-IR analysis suggested a bi-dentate chelation in all complexes, which takes place through the N-azo and O-carbonyl groups. Based on the measurement of magnetic moments and spectral analysis, a distorted octahedral geometry was proposed for Ni(II) and Cu(II) complexes, whereas zinc complex showed a hexa-coordinated geometry. The optical band gaps of the nickel(II), copper(II) and zinc(II) complexes were found to be 1.91, 2.50, and 1.96 eV, respectively, which means that they can be employed as semiconductors and that they are in the same range as highly effective photovoltaic materials. The Urbach energy parameters were also estimated from other optical parameters. The biological activity of azodicarbonamide and its synthesized complexes has been screened against the selected gram bacteria (+ve) and fungi.

Herein, a new wave of bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a, 23i, 23j, 23l, and 23n displayed the highest antiproliferative activities against the two cell lines with IC50 values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a, 23d, 23h, 23i, 23j, 23l, 23 m, and 23n showed the highest VEGFR-2 inhibitory activities with IC50 values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC50 = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).

Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4–24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59–14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI50) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC50) of 2.97 and 6.94 μM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC50 = 0.2 and 0.19 μM, respectively) and HER2 (IC50 = 0.13 and 0.07 μM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity.

There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC50 range is 2.1 − 9.8 µM), comparing to sorafenib (IC50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC50 range is 2.9 − 5.4 µM), comparing to sorafenib (IC50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression of tumour propagation. Accordingly, two series of new 3-methylquinoxaline derivatives have been designed and synthesised as VEGFR-2 inhibitors. The synthesised derivatives were evaluated in vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the VEGFR-2 inhibitory activities of the target compounds were estimated to indicate the potential mechanism of their cytotoxicity. To a great extent, the results of VEGFR-2 inhibition were highly correlated with that of cytotoxicity. Compound 27a was the most potent VEGFR-2 inhibitor with IC50 of 3.2 nM very close to positive control sorafenib (IC50 = 3.12 nM). Such compound exhibited a strong cytotoxic effect against MCF-7 and HepG2, respectively with IC50 of 7.7 and 4.5 µM in comparison to sorafenib (IC50 = 3.51 and 2.17 µM). In addition, compounds 28, 30f, 30i, and 31b exhibited excellent VEGFR-2 inhibition activities (IC50 range from 4.2 to 6.1 nM) with promising cytotoxic activity. Cell cycle progression and apoptosis induction were investigated for the most active member 27a. Also, the effect of 27a on the level of caspase-3, caspase-9, and BAX/Bcl-2 ratio was determined. Molecular docking studies were implemented to interpret the binding mode of the target compounds with the VEGFR-2 pocket. Furthermore, toxicity and ADMET calculations were performed for the synthesised compounds to study their pharmacokinetic profiles

The overexpression of matrix metalloproteinase-9 (MMP-9) is associated with tumor development and angiogenesis, and hence, it has been considered an attractive drug target for anticancer therapy. To assist in drug design endeavors for MMP-9 targets, an in silico study was presented to investigate whether our compounds inhibit MMP-9 by binding to the catalytic domain, similar to their inhibitor or not. For that, in the initial stage, a deep-learning algorithm was used for the predictive modeling of the CHEMBL321 dataset of MMP-9 inhibitors. Several regression models were built and evaluated based on R2, MAE MSE, RMSE, and Loss. The best model was utilized to screen the drug bank database containing 9,102 compounds to seek novel compounds as MMP-9 inhibitors. Then top high score compounds were selected for molecular docking based on the comparison between the score of the reference molecule. Furthermore, molecules having the highest docking scores were selected, and interaction mechanisms with respect to S1 pocket and catalytic zinc ion of these compounds were also discussed. Those compounds, involving binding to the catalytic zinc ion and the S1 pocket of MMP-9, were considered preferentially for molecular dynamics studies (100 ns) and an MM-PBSA (last 30 ns) analysis. Based on the results, we proposed several novel compounds as potential candidates for MMP-9 inhibition and investigated their binding properties with MMP-9. The findings suggested that these compounds may be useful in the design and development of MMP-9 inhibitors in the future.

Cyclic imides containing 3-benzenesulfonamide, oxime, and β-phenylalanine derivatives were synthesised and evaluated to elucidate their in vivo anti-inflammatory and ulcerogenic activity and in vitro cytotoxic effects. Most active anti-inflammatory agents were subjected to in vitro COX-1/2 inhibition assay. 3-Benzenesulfonamides (2–4, and 9), oximes (11–13), and β-phenylalanine derivative (18) showed potential anti-inflammatory activities with 71.2–82.9% oedema inhibition relative to celecoxib and diclofenac (85.6 and 83.4%, respectively). Most active cyclic imides 4, 9, 12, 13, and 18 possessed ED50 of 35.4–45.3 mg kg−1 relative to that of celecoxib (34.1 mg kg−1). For the cytotoxic evaluation, the selected derivatives 2–6 and 8 exhibited weak positive cytotoxic effects (PCE = 2/59–5/59) at 10 μM compared to the standard drug, imatinib (PCE = 20/59). Cyclic imides bearing 3-benzenesulfonamide (2–5, and 9), acetophenone oxime (11–14, 18, and 19) exhibited high selectivity against COX-2 with SI > 55.6–333.3 relative to that for celecoxib [SI > 387.6]. β-Phenylalanine derivatives 21–24 and 28 were non-selective towards COX-1/2 isozymes as indicated by their SI of 0.46–0.68.

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 2–13 against human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII, was evaluated. hCA I was efficiently inhibited by compounds 2–13 with inhibition constants (KIs) ranging from 57.8–740.2 nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with KIs between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2–13 with KI values ranging from 7.1 to 93.6 nM. Compounds 2, 3, 4, 8, 9, and 12 also exerted potent inhibitory action against hCA XII (KIs ranging from 3.1 to 20.2 nM). Molecular docking studies for the most potent compounds 2 and 3 were conducted to exhibit the binding mode towards hCA isoforms as a promising step for SAR analyses which showed similar interaction with co-crystallized ligands. As such, a subset of these mercaptoquinazolin-4(3H)-one compounds represented interesting leads for developing new efficient and selective carbonic anhydrase inhibitors (CAIs) for the management of a variety of diseases including glaucoma, epilepsy, arthritis and cancer.

Hepatocellular carcinoma (HCC) is on the rise worldwide, and its incidence in diabetic patients is two to three times that of non-diabetics. Current therapeutic options fail to provide considerable survival benefits to patients with HCC. There is a strong possibility that the FDA-approved antidiabetic combination of empagliflozin and metformin could show complementary effects to control HCC progression. However, their multitarget effects have not yet been studied on HCC development. Therefore, the present study aims to evaluate the antitumorigenic activity of this combination in non-diabetic mice with diethylnitrosamine-induced HCC. Empagliflozin/metformin combination prolonged survival and improved histological features of mice livers. Additionally, Empagliflozin/metformin showed anti-inflammatory potential and relieved oxidative stress. On the one hand these effects are likely attributed to the ability of metformin to inactivate NF-κB in an AMPK-dependent mechanism and on the other hand to the ability of the empagliflozin to inhibit the MAPKs, p38 and ERK1/2. Empagliflozin also showed a less robust effect on AMPK than that of metformin. Moreover, empagliflozin enhanced the autophagy inducing activity of metformin. Furthermore, empagliflozin/metformin exhibited increased apoptotic potential. Consequently, empagliflozin augmented the antitumorigenic function of metformin by exerting better control of angiogenesis, and metastasis. To conclude, our findings suggest empagliflozin as an ideal adjunct to metformin for the inhibition of HCC progression. In addition, since the incidence of hypoglycemia is minimal due to insulin-independent mechanism of action of both treatments, empagliflozin/metformin could be a promising therapeutic modality for the management of diabetic patients with HCC; and even non diabetic ones.

HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic due to the high transmission and mortality rate of this virus. The world health and economic sectors have been severely affected by this deadly virus, exacerbated by the lack of sufficient efficient vaccines. The design of effective drug candidates and their rapid development is necessary to combat this virus. In this study, we selected 23 antimicrobial peptides from the literature and predicted their structure using PEP-FOLD 3.5. In addition, we docked them to the SARS-CoV-2 spike protein receptor-binding domain (RBD) to study their capability to inhibit the RBD, which plays a significant role in virus binding, fusion and entry into the host cell. We used several docking programs including HDOCK, HPEPDOCK, ClusPro, and HawkDock to calculate the binding energy of the protein-peptide complexes. We identified four peptides with high binding free energy and docking scores. The docking results were further verified by molecular dynamics (MD) simulations to characterize the protein-peptide complexes in terms of their root-mean-square fluctuation (RMSF), root-mean-square deviation (RMSD), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond formation. Allergenicity and toxicity predictions suggested that the peptides we identified were non-allergenic and non-toxic. This study suggests that these four antimicrobial peptides could inhibit the RBD of SARS-CoV-2. Future in vitro and in vivo studies are necessary to confirm this.

Coronavirus disease 2019 (COVID-19) is a recent epidemic disease caused by severe acute respiratory syndrome virus type 2 (SARS-CoV-2). In pregnancy, SARS-Cov-2 infection creates additional alarm due to concerns regarding the potential for transmission from the mother to the baby during both the antenatal and postpartum times. In general, breastfeeding is seldom disallowed because of infection of the mother. However, there are few exceptions with regards to certain infectious organisms with established transmission evidence from mother to infant and the link of infection of a newborn with significant morbidity and mortality. It is confirmed that pregnant women can become infected with SARS-CoV-2, although the debate on the possible vertical transmission of SARS-CoV-2 infection during pregnancy is still open. In this regard, the literature is still poor. On the contrary, the information on the safety of breastfeeding even during infections seems reassuring when the mother takes the necessary precautions. However, there are still answered questions regarding the precautions to be taken during breastfeeding by COVID-19 patients. This paper reviews the existing answers to these and many other questions. This review therefore presents a summary of the present-day understanding of infection with SARS-CoV-2 and discusses the answers around the maternal transmission of COVID-19 and the potential threat of breastfeeding to babies born to infected pregnant mothers. In conclusion, intrauterine transmission of SARS-CoV-2 infection is less likely to occur during pregnancy. Most studies suggest that COVID-19 is not transmitted through breast milk. Correspondingly, COVID-19-infected neonates might acquire the infection via the respiratory route because of the postnatal contact with the mother rather than during the prenatal period. International organizations encourage breastfeeding regardless of the COVID-19 status of the mother or child as long as proper hygienic and safety measures are adhered to so as to minimize the chance of infant infection by droplets and direct contact with the infected mother. Pasteurized donor human milk or infant formula as supplemental feeding can be quite beneficial in the case of mother–infant separation till breastfeeding is safe.