Screening and toxicity evaluation of natural compounds as adenosine 2a and 2b receptor ligands: insights from molecular docking, dynamics, and ADMET analysis.

Recent studies suggest that immunological and inflammatory responses in cardiovascular disorders, such as hypertension, myocardial infarction, ischemia injury, heart failure, arrhythmias, and atherosclerosis, may be affected by changes in the adenosine system. Pharmacological modulation of adenosine occurs through its receptor subtypes. In numerous preclinical studies, the activation of adenosine receptor 2A (A2AR) or the blockade of adenosine receptor 2B (A2BR) has shown promising results against cardiovascular diseases. This in silico study aimed to identify potential natural compounds that can activate A2AR or block A2BR without causing toxicity. Natural compounds were screened using COlleCtion of Open Natural ProdUcTs (COCONUT) or Natural Product Activity and Species Source Database (NPASS) databases to find agonists for A2AR or an antagonists/inverse agonists for A2BR. These compounds were then pre-filtered based on their toxicity profiles. The remaining compounds were subjected to molecular docking against A2AR and A2BR followed by molecular dynamics simulations were conducted. Finally, selected compounds' ADMET properties were determined using ADMETlab 2.0 web tool. Ultimately, one novel natural compound with potential agonistic activity (COCONUT IDs: CNP0450901) for A2AR and one antagonist/inverse agonist (rauwolscine) for A2BR were identified.

Exploring New 5-Nitroimidazole Derivatives As Potent Acetylcholinesterase and Butyrylcholinesterase Enzyme Inhibitors.

Discovering new compounds capable of inhibiting physiologically and metabolically significant drug targets or enzymes is of paramount importance in biological chemistry. With this aim, new 5-nitroimidazole derivatives (1-4) were designed and synthesized, and their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were discovered using acetyl (butyryl) thiocholine and Ellman's reagents for spectrophotometric assay. The inhibitory profiles of the synthesized compounds were assessed by comparing their IC50 and Ki values. Results demonstrate significant inhibitory activity of all synthesized compounds against both AChE and BuChE compared to the reference compound, donepezil. Notably, compound 4 exhibited dual inhibition of these enzymes, showing the highest activity against Electrophorus electricus AChE (EeAChE) with a Ki value of 0.024±0.009 nM and against equine BuChE (eqBuChE) with a Ki value of 0.087±0.017 nM. Furthermore, molecular modeling was conducted to study the interaction modes of the most potent compound (4) and donepezil in the active site of their related enzymes' crystal structures (PDB ID: 4EY7 and 4BDS, respectively). Additionally, drug-likeness, ADME, and toxicity profiles of the compounds and metronidazole were predicted. The above results indicated that the dual inhibition of these enzymes is considered as a promising strategy for the treatment of neurological disorder especially Alzheimer's disease.

Exploring Natural Compounds Targeting PD-L1 and STAT3: Toxicogenomic Analysis, Virtual Screening, Molecular Docking, ADMET Evaluation, and Biological Activity Prediction.

BACKGROUND: One of the most important targets in cancer immunotherapy is programmed cell death ligand 1 (PD-L1). Monoclonal antibodies developed for this target have disadvantages due to their low bioavailability and some immune-related adverse effects. Additionally, small molecules targeting PD-L1 are still in the experimental stage. At this point, discovering non-toxic natural compounds that directly or indirectly target PD-L1 is essential. In this in silico study, a comprehensive literature search was conducted to identify publications reporting the master regulator of PD-L1, which was suggested as a Signal Transducer and Activator of Transcription 3 (STAT3). The relationship between STAT3 and PD-L1 was further investigated through bioinformatic analysis. METHOD: Subsequently, natural compounds targeting PD-L1 and STAT3 were screened, and compounds with suitable toxicity profiles were docked against both PD-L1 and STAT3. Following molecular docking, the selected molecules underwent DNA docking, ADMET profile analysis, and in silico assessment of biological activities. The relationship between PD-L1 and STAT3 was determined in 52 out of the 453 articles, and it was further demonstrated in genegene interactions. Following the virtual screening, 76 natural compounds were identified, and after pre-filtering based on physicochemical properties, drug-likeness, and ADMET profiles, 29 compounds remained. RESULT: Subsequent docking revealed that two compounds, 6-Prenylapigenin, and Gelomulide J, persisted. ADMET and biological activity prediction results suggested that 6-Prenylapigenin is non-toxic and has the potential to inhibit PD-L1 and STAT3 in silico. The present study highlights that STAT3 serves as the master regulator of PD-L1, and it further suggests that 6- Prenylapigenin exhibits the potential to modulate PD-L1 and/or STAT3. CONCLUSION: This finding could pave the way for the development of small molecules designed to block the PD-1/PD-L1 interaction by silencing the PD-L1 and/or STAT3 genes or reducing protein levels.

Structure-based inhibition of acetylcholinesterase and butyrylcholinesterase with 2-Aryl-6-carboxamide benzoxazole derivatives: synthesis, enzymatic assay, and in silico studies.

An important research topic is the discovery of multifunctional compounds targeting different disease-causing components. This research aimed to design and synthesize a series of 2-aryl-6-carboxamide benzoxazole derivatives that inhibit cholinesterases on both the peripheral anionic and catalytic anionic sides. Compounds (7-48) were prepared from 4-amino-3-hydroxybenzoic acid in three steps. The Ellman test, molecular docking with Maestro, and molecular dynamics simulation studies with Desmond were done (Schrodinger, 12.8.117). Compound 36, the most potent compound among the 42 new compounds synthesized, had an inhibitory concentration of IC50 12.62 nM for AChE and IC50 25.45 nM for BChE (whereas donepezil was 69.3 nM and 63.0 nM, respectively). Additionally, compound 36 had docking values ​​of - 7.29 kcal/mol for AChE and - 6.71 kcal/mol for BChE (whereas donepezil was - 6.49 kcal/mol and - 5.057 kcal/mol, respectively). Furthermore, molecular dynamics simulations revealed that compound 36 is stable in the active gorges of both AChE (average RMSD: 1.98 Å) and BChE (average RMSD: 2.2 Å) (donepezil had average RMSD: 1.65 Å and 2.7 Å, respectively). The results show that compound 36 is a potent, selective, mixed-type dual inhibitor of both acetylcholinesterase and butyrylcholinesterase. It does this by binding to both the catalytically active and peripheral anionic sites of cholinesterases at the same time. These findings show that target compounds may be useful for establishing the structural basis for new anti-Alzheimer agents.

Design, synthesis and in vitro antiproliferation activity of some 2-aryl and -heteroaryl benzoxazole derivatives.

Background: Phortress produces reactive electrophilic metabolites that form DNA adducts only in sensitive tumor cells. The authors converted the 2-phenylbenzothiazole nucleus in phortress to 2-aryl and -heteroaryl benzoxazole derivatives (11 new and 14 resynthesized). All synthesized compounds were studied for antitumor activity in various cancer cells. Materials & methods: Cytotoxicity, cell morphology, flow cytometry and cell-cycle analyses of compounds were performed and more active derivatives were tested in the MCF-7 cell line. Conclusion: Methyl 2-(thiophen-2-yl)benzo[d]oxazole-6-carboxylate (BK89) has a higher effect than fluorouracil to induce apoptotic cell death (apoptosis value of 49.44%). Cell-cycle analysis shows that the compounds BK89 and methyl 2-(furan-2-yl)benzo[d]oxazole-6-carboxylate (BK82) can be used as potential cell-cycle blockers by arresting MCF-7 cells in G0/G1 phase at rates of 63% and 85%, respectively.

There is an urgent need to develop potent and selective anticancer agents. In this study, the design and applications of compounds sensitive to specific cancer cells and targeting cancer cells were investigated. The results show that the synthesized compounds can be antiproliferative drug candidates for breast cancer. These compounds may shed light on cancer treatment and cancer research.

A novel class for carbonic anhydrases inhibitors and evaluation of their non-zinc binding.

In this study, 23 different imidazole derivatives were synthesized, and the inhibitory properties of these derivatives against carbonic anhydrase I and II isoenzymes were investigated for the first time. The inhibition concentrations of the imidazole derivatives were found to be in the range of 2.89-115.5 nM. Docking studies examined the binding properties of the imidazole derivatives, and the structure-activity relationship is discussed. Theoretical calculations showed that the binding mode of the imidazole ring was non-zinc binding.

Excited State Intramolecular Proton Transfer (ESIPT)-Based Sensor for Ion Detection.

C-2 and C-5 substituted imidazole skeleton was synthesized through a one-pot two-step strategy. Synthesized molecule emits the light on ESIPT (excited-state intramolecular proton transfer). This molecule was utilized for its proton donor ability, and we have observed that fluoride and cyanide ions can be detected selectively. Different cations and anions were selected to observe the response of the synthesized molecule. However, there were not any fluorometric and colorimetric response except for fluoride and cyanide ions. Detection limits of fluoride and cyanide ions were found to be 9.22 µM and 11.48 µM, respectively. 1H-NMR spectra for the solution of the sensor and TBAF (tetrabuthylammoniumfluoride) were used for the identification of [L]-[HF2]- species. 3 equiv. TBAF saturated the solution of the sensor in d6-DMSO, and some of the proton resonances shifted to upfield due to the through-bond effect. The disappearance of NH proton with 0.5 equiv. TBAF or TBACN (tetrabuthylammoniumcyanide) showed that there was a proton abstraction by fluoride and cyanide ions, instead of the hydrogen bond. Solid-state application was utilized, and paper test strips were applied. Emission differences emerged when the sensor loaded strips were reacted with TBAF. Time resolved experiments revealed that solution of the sensor and TBAF in DMSO have multiexponential decay, and one of the lifetime was measured as 13.4 ns.

New-Generation Benzimidazole-Based Plasmid Delivery Reagents with High Transfection Efficiencies on the Mammalian Cells.

Gene transfer and gene therapy studies require high-efficiency gene delivery reagents. By transferring the piece of DNA that we are interested in, we can alter the expression of certain gene or genes to further characterize its role in the cell function or in the organism's development, metabolism, immune system, etc. Transfection reagents that enable efficient delivery of the DNA to the cells are important tools in the molecular and cellular biology studies. There are chemical products and tools that have been used for transfection of the cells but they are not as efficient as desired or they can induce cytotoxicity. It is crucial to design and generate new transfection reagents to further support the field of biotechnology, molecular studies, cellular biology, and in vitro studies relying on them. The more efficient and the less cytotoxic compounds will be especially useful for the field. We synthesized a new set of benzimidazole-based transfection reagents that have higher efficiency to carry GFP expressing plasmid in to the mammalian cells compared with the commercially available ones with low cytotoxicity. GFP expression levels were tracked by flow cytometry to determine the transfection efficiencies. Benzimidazole-based transfection reagents can be safely used for transfection studies in tissue culture as well as in gene therapy applications due to their high efficiency in the gene transfer to the mammalian cells.

Mono- or di-substituted imidazole derivatives for inhibition of acetylcholine and butyrylcholine esterases.

Mono- or di-substituted imidazole derivatives were synthesized using a one-pot, two-step strategy. All imidazole derivatives were tested for AChE and BChE inhibition and showed nanomolar activity similar to that of the test compound donepezil and higher than that of tacrine. Structure activity relationship studies, docking studies to on X-ray crystal structure of AChE with PDB code 1B41, and adsorption, distribution, metabolism, and excretion (ADME) predictions were performed. The synthesized core skeleton was bound to important regions of the active site of AChE such as the peripheral anionic site (PAS), oxyanion hole (OH), and anionic subsite (AS). Selectivity of the reported test compounds was calculated and enzyme kinetic studies revealed that they behave as competitive inhibitors, while two of the test compounds showed noncompetitive inhibitory behavior. ADME predictions revealed that the synthesized molecules might pass through the blood brain barrier and intestinal epithelial barrier and circulate freely in the blood stream without binding to human serum albumin. While the toxicity of one compound on the WS1 (skin fibroblast) cell line was 1790 µM, its toxicity on the SH-SY5Y (neuroblastoma) cell line was 950 µM.

Synthesis of novel imidazopyridines and their biological evaluation as potent anticancer agents: A promising candidate for glioblastoma.

Novel imidazopyridine derivatives were synthesized according to a very simple protocol and then subjected to cytotoxicity testing against LN-405 cells. Two of the compounds exhibited antiproliferative effects on LN-405 cells at 10 and 75 µM and were selected as lead compounds for further study. Safety experiment for lead compounds on WS1 was carried out and IC50 values were calculated as 480 and 844 µM. LN-405 cell line were incubated with the lead compounds and then tested for DNA damage by comet assay and effects on cell cycle using flow cytometry. The results of these two tests showed that both lead compounds affected the G0/G1 phase and did not allow the cells to reach the synthesis phase. The log BB (blood-brain barrier) and Caco-2 permeability of the synthesized molecules were calculated and it was shown that imidazopyridine derivatives taken orally are likely to pass through gastrointestinal membrane and the blood-brain barrier.

Indole-containing new types of dyes and their UV-vis and NMR spectra and electronic structures: Experimental and theoretical study.

Indole containing dyes were synthesized via a simple method with high yield. These molecules have different colors and UV-vis spectra of them were recorded. Impact of solvents on absorbances was investigated and it was observed that basic solvent such as DMF and pyridine have blue shift. TD-DFT calculations were done and results were compared with experimental data. NMR data of molecules were analyzed and tautomeric forms of colorants and their ratio were determined. It was find out that two tautomers might be formed in solution, called indole and indolenine form. HOMO-LUMO and energy gaps were calculated and plotted. Furthermore, molecular electrostatic potentials were simulated to find out electrophilic and nucleophilic regions.