Preparation and optimization of glyceryl monooleate-low molecular weight chitosan nanoparticles for delivery of morpholinopyrrolizine derivative

Purpose: To develop and optimize glyceryl monooleate–low-molecular-weight chitosan (GMO-LMWC) nanoparticles loaded with morpholinopyrrolizine derivative (NPM). Methods: Molecular mechanics was used to determine the main driving force for the complexation between glyceryl monooleate (GMO) and chitosan. Nanoparticles were fabricated using a modified film-rehydration method. Optimization was carried out using a statistical design approach. The effects of formulation factors (concentrations of GMO, LMWC and Tween 80) on zeta potential and particle size were investigated using a 23 factorial design. Results: A steady increase in binding energy was observed when chitosan length was increased from 22 to 142 Å, and thereafter it remained almost constant. The examined independent variables had significant effects on particle size and zeta potential. The particle size of the nanoparticles varied from 265 to 1270 nm while zeta potential was in the range of 3 – 12 mV. The optimized preparation showed a significantly low half-maximal inhibitory concentration (IC50) when compared to a free anticancer agent in the hepatocellular carcinoma (HePG-2) cell line. Conclusion: A nanoparticulate system composed of GMO and LMWC is a potential nanocarrier for delivery of morpholinopyrrolizine derivative

Formulation, characterization and in-vitro evaluation of solid lipid nanoparticles for the delivery of a new anticancer agent, 1H-pyrazolo[3,4-d] pyrimidine derivative

Purpose: To investigate the physicochemical properties and in vitro cytotoxic effect of a potent epidermal growth factor receptor-tyrosine kinase (EGFRWT-TK) inhibitor, 1H-pyrazolo [3,4-d] pyrimidine (FEP) derivative and formulated as solid lipid nanoparticles (SLNs) using stearic acid (ST) or glycerylmonostearate (GMS). Methods: The SLNs were prepared by hot homogenization and sonication method. The effect of formulation variables on particle size, zeta potential and polydispersity index (PDI) of SLNs were studied, and an optimized formulation selected. Drug-excipient interactions were assessed by differential scanning calorimetry (DSC) and Fourier Transform Infrared (FTIR). Mammary gland breast cancer (MCF-7) and human colon cancer (HCT116) human cell lines were used to evaluate the cytotoxic activity of the free and FEP-loaded SLNs. Results: The particle size of the SLNs was in the range of 138 - 819 nm, while zeta potential varied from -15 to -20 nm. FEP-loaded SLNs exhibited significant cytotoxic effect compared to the free drug and doxorubicin in the two cell lines (p < 0.05). The activity was higher in HCT116 compared with MCF-7 cells (p < 0.007). The concentration of FEP loaded SLNs, free drug and doxorubicin that showed 50 % inhibition (IC50) for breast cancer cells were 1.06 ± 0.09, 2.58 ± 0.16 and 3.75 ± 0.4 μg/ml, respectively. Conclusion: The findings show that FEP-loaded SLNs have greater in-vitro cytotoxic activity than the free FEP, and thus, might improve cancer therapy in humans

An Eco-Friendly Technique: Solvent-Free Microwave Synthesis and Docking Studies of Some New Pyridine Nucleosides and Their Pharmacological Significance

Two series of novel 5-arylazo-3-cyano-2-(2″,3″,4″,6″-tetra-O-acetyl-β-d-galacto pyranosyloxy) pyridines and 3-cyano-2-(2″,3″,4″,6″-tetra-O-acetyl-β-d-galactopyranosyloxy) pyridines were synthesized in high yields utilizing a microwave-assisted synthesis tool guided by the principles of green chemistry. The chemical structures of the new substances were confirmed on the basis of their elemental analysis and spectroscopic data (FT-IR, 1D, 2D-NMR). Activity against different bacterial strains was studied. The anticancer potential of the new compounds is also discussed. Molecular docking was used as a tool in this research work to get better insight into the possible interactions, affinities, and expected modes of binding of the most promising derivatives of the potential chemotherapeutic target (DHFR)

Design of new captopril mimics as promising ACE inhibitors: ADME, pharmacophore, molecular docking and dynamics simulation with MM-PBSA and PCA calculations

New pyrrolidine derivatives with more than 50% structural similarity with captopril were designed to get new captopril mimics with superior potential to act on both peripheral and central ACE. Further optimization was carried out through pharmacophoric mapping, then pharmacokinetics of these compounds were analyzed, 42 derivatives were selected for further study, as they exhibited potential to pass through BBB. Molecular docking on ACE using captopril and lisinopril as reference drugs was performed, and Compound 28 (2-Pyrrolidin-2-ylidene-N-thiomorpholin-4-ylmethyl-malonamic acid ethyl ester) showed the best docking scores, proving its superiority over captopril and comparability to lisinopril. Further molecular dynamics simulations and energy calculations demonstrated binding stability and close mimicry to both drugs. The results indicate that Compound 28 is a promising candidate for further investigations as a potential drug to act centrally and peripherally. Compound 28 can be synthesized by reacting Cyano-pyrrolidin-2-ylidene-acetic acid ethyl ester through Mannich reaction with thiomorpholine and formaldehyde

Evaluating the ability of some natural phenolic acids to target the main protease and AAK1 in SARS COV-2

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

Crop Yield Prediction Using Multi Sensors Remote Sensing (Review Article)

Pre-harvest prediction of a crop yield may prevent a disastrous situation and help decision-makers to apply more reliable and accurate strategies regarding food security. Remote sensing has numerous returns in the area of crop monitoring and yield prediction which are closely related to differences in soil, climate, and any biophysical and biochemical changes. Different remote techniques could be used for crop monitoring and yield prediction including multi and hyper spectral data, radar and lidar imagery. This study reviews the potentialities, advantages and disadvantages of each technique and the applicability of these techniques under different agricultural conditions. It also shows the different methods in which these techniques could be used efficiently. In addition, the study expects future scenarios of remote sensing applications in vegetation monitoring and the ways to overcome any obstacles that may face this work. It was found that using satellite data with high spatial resolution are still the most powerful method to be used for crop monitoring and to monitor crop parameters. Assessment of crop spectroscopic parameters through field or laboratory devices could be used to identify and quantify many crop biochemical and biophysical parameters. They could be also used as early indicators of plant infections; however, these techniques are not efficient for crop monitoring over large areas

Tolmetin Sodium Fast Dissolving Tablets for Rheumatoid Arthritis Treatment: Preparation and Optimization Using Box-Behnken Design and Response Surface Methodology

Tolmetin sodium (TLM) is a non-steroidal anti-inflammatory drug (NSAIDs). TLM is used to treat inflammation, skeletal muscle injuries, and discomfort associated with bone disorders. Because of the delayed absorption from the gastro intestinal tract (GIT), the currently available TLM dosage forms have a rather protracted start to the effect, according to pharmacokinetic studies. The aim of this study was to create a combination for TLM fast dissolving tablets (TLM-FDT) that would boost the drug’s bioavailability by increasing pre-gastric absorption. The TLM-FDTs were developed using a Box-Behnken experimental design with varied doses of crospovidone (CP), croscarmellose sodium (CCS) as super-disintegrants, and camphor as a sublimating agent. In addition, the current study used response surface approach to explore the influence of various formulation and process factors on tablet qualities in order to verify an optimized TLM-FDTs formulation. The optimized TLM-FDTs formula was subsequently evaluated for its in vivo anti-inflammatory activity. TLM-FDTs have good friability, disintegration time, drug release, and wetting time, as well as fast disintegration and dissolution behavior. Significant increase in drug bioavailability and reliable anti-inflammatory efficacy were also observed, as evidenced by considerable reductions in paw thickness in rats following carrageenan-induced rat paw edema. For optimizing and analyzing the effect of super-disintegrants and sublimating agents in the TLM-FDTs formula, the three-factor, three-level full factorial design is a suitable tool. TLM-FDTs are a possible drug delivery system for enhancing TLM bioavailability and could be used to treat rheumatoid arthritis

Phytoconstituents of Butterbur (P. japonicus), their metabolic pathway and ability to modulate bone morphogenic protein (BMP) signaling

ABSTRACTA library of natural sesquiterpene and phenolic compounds from Petasites japonicus are being investigated through different computational techniques to study their ability to target BMP. Lipinski rule, ADMET, molecular docking studies and metabolism were used to reach promising candidates with proposed activity against BMP. Four sesquiterpenes (kablicin, petisinol, bakkenolide D and bakkenolide IIIa) and four phenolic compounds exhibited drug-like properties (caffeic acid, petasiphenol, petasitesin A and petasitesin B), so they deserve further clinical exploration as bone loss modulators. The phenolic compounds specially fukinolic acid and petasiphenol showed lower binding energy with both BMPRIA and BMPRII than Icariin agonist and sesquiterpenes. Bakkenolide IIIa showed dual potential on both BMPRIA and BMPRII with binding energies equal – 7.82 and – 9.9 Kcal/mol respectively, which is more better score than Betulinic acid agonist. This research is focusing on plant-human interactions and exploring the ability of plant constituents to modulate a human protein such as BMP

Microwave-Assisted Synthesis, Biological Activity Evaluation, Molecular Docking, and ADMET Studies of Some Novel Pyrrolo [2,3-b] Pyrrole Derivatives

Novel pyrrolo [2,3-b] pyrrole derivatives were synthesized and their hypolipidemic activity was assessed in hyperlipidemic rats. The chemical structures of the new derivatives were confirmed through spectral analysis. Compounds 5 and 6 were revealed to be the most effective hypolipidemic agents, with considerable hypocholesterolemic and hypotriglyceridemic effects. They appear to be promising candidates for creating new powerful derivatives with anti-atherosclerotic and hypolipidemic properties. As for antimicrobial activity, some of the tested compounds showed moderate activity against Pseudomonas aeruginosa: compound 2 revealed an MIC value of 50 μg/mL, compared to 25 μg/mL for ciprofloxacin. Compound 3 showed good antimicrobial activity against Staphylococcus aureus, comparable to ciprofloxacin, and roughly half the activity of ampicillin, according to MIC values. Compound 2 has an MIC approximately 25% of that of clotrimazole against Candida albicans. Compound 2 also showed the highest antioxidant activity with 59% inhibition of radical scavenging activity. Additionally, the cytotoxic activity of these new derivatives 1–7 was investigated and most of them showed good anticancer activity against the three tested cell lines

Anticoagulants as Potential SARS-CoV-2 Mpro Inhibitors for COVID-19 Patients: In Vitro, Molecular Docking, Molecular Dynamics, DFT, and SAR Studies

In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 Mpro. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds. Moreover, a quantum mechanical study was also conducted which helped us to attest to some of the molecular docking and dynamics findings. A biological evaluation (in vitro) of the most promising compounds was also performed by carrying out the MTT cytotoxicity assay and the crystal violet assay in order to assess inhibitory concentration 50 (IC50). It is worth noting that ticagrelor displayed the highest intrinsic potential for the inhibition of SARS-CoV-2 with an IC50 value of 5.60 µM and a safety index of 25.33. In addition, fondaparinux sodium and dabigatran showed promising inhibitory activities with IC50 values of 8.60 and 9.40 µM, respectively, and demonstrated safety indexes of 17.60 and 15.10, respectively. Moreover, the inhibitory potential of the SARS-CoV-2 Mpro enzyme was investigated by utilizing the SARS-CoV-2 Mpro assay and using tipranavir as a reference standard. Interestingly, promising SARS-CoV-2 Mpro inhibitory potential was attained for fondaparinux sodium with an IC50 value of 2.36 µM, surpassing the reference tipranavir (IC50 = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 Mpro inhibitory potential was attained for dabigatran with an IC50 value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches