In-silico study MM/GBSA binding free energy and molecular dynamics simulation of some designed remdesivir derivatives as the inhibitory potential of SARS-CoV-2 main protease.

Background and purpose: Coronavirus disease (COVID-19) is one of the greatest challenges of the twentieth century. Recently, in silico tools help to predict new inhibitors of SARS-CoV-2. In this study, the new compounds based on the remdesivir structure (12 compounds) were designed. Experimental approach: The main interactions of remdesivir and designed compounds were investigated in the 3CLpro active site. The binding free energy of compounds by the MM-GBSA method was calculated and the best compound (compound 12 with the value of -88.173 kcal/mol) was introduced to the molecular dynamics simulation study. Findings/Results: The simulation results were compared with the results of protein simulation without the presence of an inhibitor and in the presence of remdesivir. Additionally, the RMSD results for the protein backbone showed that compound 12 in the second 50 nanoseconds has less fluctuation than the protein alone and in the presence of remdesivir, which indicates the stability of the compound in the active site of the Mpro protein. Furthermore, protein compactness was investigated in the absence of compounds and the presence of compound 12 and remdesivir. The Rg diagram shows a fluctuation of approximately 0.05 A, which indicates the compressibility of the protein in the presence and absence of compounds. The results of the RMSF plot also show the stability of essential amino acids during protein binding. Conclusion and implications: Supported by the theoretical results, compound 12 could have the potential to inhibit the 3CLpro enzyme, which requires further in vitro studies and enzyme inhibition must also be confirmed at protein levels.

Correction: DCID-mediated esterification of carboxylic acids with alcohols under mild conditions.

[This corrects the article DOI: 10.1039/D3RA04048H.].

DCID-mediated esterification of carboxylic acids with alcohols under mild conditions.

DCID (Dichloroimidazolidinedione) 2 is used as a novel coupling reagent for the esterification of carboxylic acids with alcohols at room temperature. The reaction represents the first DCID-promoted esterification under mild conditions with good to excellent yields. Reactions can proceed smoothly with those bearing electron-withdrawing and donating group(s) on the carboxylic acids and benzyl alcohols at ambient temperature. Furthermore, we proposed a plausible mechanism and confirmed it by isolating and characterizing intermediates 3a and 7. The structures of the synthesized compounds were confirmed by comparison of melting points and NMR spectra.

A universal ratiometric method for Micro-RNA detection based on the ratio of electrochemical/electrochemiluminescence signal, and toehold-mediated strand displacement amplification.

An ultra-selective and reproductive ratiometric platform was introduced based on the ratio of Ru(phen)32+ electrochemiluminescence (ECL) signal and methylene blue (MB) electrochemistry (EC) signal, which was amplified using a specific and efficient toehold-mediated strand displacement (TMSD). The stable DNA nanoclews (NCs) were efficiently loaded with MB (MB-NCs) as EC signal tags after being synthesized utilizing a simple rolling circle amplification reaction. Besides, Ti3C2-based nanocomposite could apply as a superb carrier for both Ru(phen)32+ and gold nanoparticles (Ti3C2-Au-Ru), resulting in a nearly constant ECL internal reference to eliminate the possible interferences. The Ti3C2-Au-Ru was attached to the surface of the electrode using Nafion, which exhibited excellent conductivity, and hairpin DNAs (hDNAs) were fixed on AuNPs via an Au-S bond. The designed biosensor was finally applied for miRNA-18a detection as a target model. The TMSD method made it possible to concurrently convert and amplify a single miRNA-18ainput into a large amount of output DNAs with high selectivity. These output DNAs were designed to unfold the stem-locked area of hDNAs. The opened hDNAs then hybridized with the MB-NCs to produce an EC signal. In the proposed biosensing system, by raising the target concentration of miRNA, the EC signal gradually rose, the ECL signal remained nearly constant, and the ratiometric detection method markedly promoted biosensor accuracy. Linear correlations of the ratio value of the EC/ECL with miRNA-18a concentrations between 20 aM and 50 pMwere observed, with the limit of detection of 9 aM. The biosensor was applied to detect miRNA-18a in real serum samples with satisfactory results.

Novel spiro[indene-1,2'-quinazolin]-4'(3'H)-one derivatives as potent anticonvulsant agents: One-pot synthesis, in vivo biological evaluation, and molecular docking studies.

A new series of spiro[indene-1,2'-quinazolin]-4'(3'H)-one derivatives 4a-m were synthesized via a one-pot method and evaluated for anticonvulsant activities using pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. Obtained results demonstrated that these compounds have not anticonvulsant activity in PTZ test while are active in the MES test. Among the synthesized compounds, the best anticonvulsant activity was obtained with compound 4h. This compound also was not neurotoxic. Given that the title new compounds have the pharmacophore requirement for benzodiazepine (BZD) receptor agonist, the most potent compound was assayed in vivo and in silico as BZD receptor agonist. After treatment with flumazenil as a standard BZD receptor antagonist, anticonvulsant activity of compound 4h decreased. Therefore, the involvement of BZD receptors in anticonvulsant activity of this compound confirmed. Furthermore, docking study of compound 4h in the BZD-binding site of GABAA receptor confirmed that this compound interacted with the important residues.

Novel Derivatives of Tetrahydrobenzo (g) Imidazo[α-1,2] Quinoline Induce Apoptosis Via ROS Production in the Glioblastoma Multiforme Cells, U-87MG.

BACKGROUND: Despite newer therapeutic approaches against glioblastoma multiforme (GBM), the severely poor prognosis and treatment resistance are still disadvantages that slow down the patient's recovery process. Consistent with the need to develop more effective and optimized therapies to control GBM cell growth, the effects of a new series of tetrahydrobenzo(g)imidazo[α-1,2]quinolone derivatives on GBM cell growth and the underlying mechanism is investigated in the current study. METHODS: U-87MG cell line, glioblastoma multiforme and normal skin fibroblast cell line, AGO1522 were used to study the anticancer effects of 5 derivatives of tetrahydrobenzo(g)imidazo[α-1,2]quinolone and paclitaxel as a standard drug. The cytotoxic effect on cell growth was assessed using the MTT assay. Annexin V FITC staining and PI staining were applied to detect apoptosis and cell cycle distribution using flow cytometry. The extent of reactive oxygen species (ROS) formation was assessed using the fluorescent probe 7-dichlorofluorescin diacetate and caspase-3 activity using the colorimetric assay kit. RESULTS: Among the 5 derivatives of tetrahydrobenzo(g)imidazo[α-1,2]quinolone, the 5c derivative (5-(6-bromo-2-chloroquinolin-3-yl)-9a-hydroxy-8,8-dimethyl-4-Nitro-2,3,5,5a,7,8,9,9a-octahydroimidazo[α-1,2]quinoline-6(1H)) showed the strongest cytotoxic effect on U-87MG cells in a time and Dose-dependent manner compared to the other derivatives and paclitaxel. The IC50 (11.91 M) of the 5c derivative induced apoptosis accompanied by a significant increase in sub-G1 and super-G2 phases of U-87MG cells. The increased level of cellular ROS and caspase 3 activity after treatment of U-87MG cells with 5c derivative was significant compared to untreated cells. CONCLUSION: Our data provide insights into the potent anticancer effects of the 5c-derivative of tetrahydrobenzo(g)imidazo[α-1,2]quinolone on GBM cells via the caspase-dependent apoptotic pathway, which may merit further attention.

Metabolomic study of serum in patients with invasive ductal breast carcinoma with LC-MS/MS approach.

BACKGROUND: Invasive ductal carcinoma (IDC) is the most common type of breast cancer so its early detection can lead to a significant decrease in mortality rate. However, prognostic factors for IDC are not adequate and we need novel markers for the treatment of different individuals. Although positron emission tomography and magnetic resonance imaging techniques are available, they are based on morphological features that do not provide any clue for molecular events accompanying cancer progression. In recent years, "omics" approaches have been extensively developed to propose novel molecular signatures of cancers as putative biomarkers, especially in biofluids. Therefore, a mass spectrometry-based metabolomics investigation was performed to find some putative metabolite markers of IDC and potential metabolites with prognostic value related to the estrogen receptor, progesterone receptor, lymphovascular invasion, and human epidermal growth factor receptor 2. METHODS: An untargeted metabolomics study of IDC patients was performed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The multivariate principal component analysis by XCMS online built a model that could separate the study groups and define the significantly altered m/z parameters. The most important biological pathways were also identified by pathway enrichment analysis. RESULTS: The results showed that the significantly altered metabolites in IDC serum samples mostly belonged to amino acids and lipids. The most important involved pathways included arginine and proline metabolism, glycerophospholipid metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. CONCLUSIONS: Significantly altered metabolites in IDC serum samples compared to healthy controls could lead to the development of metabolite-based potential biomarkers after confirmation with other methods and in large cohorts.

Preparation and characterization of nano MnO-CaLs as a green catalyst for oxidation of styrene.

Hydrophilic nano MnO is shown to have significant stability in aqueous media for oxidation of styrene. Different catalysts have been used to synthesis styrene oxide, but MnO-CaL is considered the efficient and selective catalyst to produce styrene oxide. In general, this paper reported especial strategy for synthesis of novel nano MnO that stabilized with oleic acid in chloroform and changing nature of its stabilizer by exchanging oleic acid with lignosulfunate and displays its catalytic activity towards selective oxidation of styrene. The catalyst has shown good selectivity in oxidation of styrene by changing temperature. Finding the optimal conditions for reaction and determining the best time and temperature for achieving the ideal product and reducing the side products are among the issues discussed in this article. MnO-CaLs leads to selective oxidation of styrene to styrene epoxide at low temperature. By increasing the temperatures, benzaldehyde and partially 2-phenyl acetaldehyde are also produced as by-products. Furthermore, the nano catalyst could be recycled several times without any clear changing in activity, which makes nano catalyst economic and environmentally friendly.

Cu-metal organic frameworks (Cu-MOF) as an environment-friendly and economical catalyst for one pot synthesis of tacrine derivatives.

The present work describes the catalytic activity of Cu-MOF for the one-pot synthesis of tacrine derivatives via a four-component reaction of 2-hydroxynaphthalene-1,4-dione, aldehydes, malononitrile and cycloketones in the presence of AlCl3. The structure of the synthesized compound is confirmed by 1H NMR, 13C NMR, IR, and MASS. The catalyst prepared under pressure is characterized by powder X-ray diffraction and SEM. The noteworthy advantages of this procedure include its broad substrate scope, high yields up to 93%, atom economy, using readily available starting materials and a powerful recyclable nano catalyst. Additionally, there is no need to use column chromatography for purifying products so, it has the potential for large-scale applications in pharmaceutical industries. Another advantage of this method is the ability to recycle the catalyst up to 3 times and reuse it.

Molecular dynamics simulation and 3D-pharmacophore analysis of new quinoline-based analogues with dual potential against EGFR and VEGFR-2.

Epidermal growth factor and vascular endothelial growth factor-2 are important targets of tyrosine kinase for the treatment of various cancerous diseases. Combination of inhibition of both targets to produce synergy in the signal pathway is a critical approach to identify novel tyrosine kinase inhibitors. In this study, a series of new compounds derived from the 4-aminoquinoline as dual inhibitors were synthesized. The obtained results of cytotoxicity assay against human carcinoma cell lines indicated 0.8 µM for 4c against A549 showing its high efficiency in comparison to erlotinib. Pharmacophore modeling as a structure-based method was investigated on dual inhibitors and 4c which was compared with co-crystallized in the active site of EGFR and VEGFR-2. They have shown the same binding orientation as vandetanib, erlotinib and sorafenib. Molecular dynamics simulation results approved that Met769, Lys721, Asp1046, and Lys868 are key residues in two binding sites for dual activity. Ala1050 and Pro968 were identified as new amino acid interaction sites for dual inhibition. 4c showed more favorable stability than vandetanib in VEGFR-2 receptor for a 50 ns dynamic simulation. The high correlation between essential pharmacophoric features of designed compounds and lead inhibitors interactions provided a deeper insight into the structural basis of 4-aminoquinoline inhibition.

Extraction and Identification of Two Flavonoids in Phlomoides hyoscyamoides as an Endemic Plant of Iran: The Role of Quercetin in the Activation of the Glutathione Peroxidase, the Improvement of the Hydroxyproline and Protein Oxidation in Bile Duct-Ligated Rats.

BACKGROUND: Cholestatic liver disease, a serious chronic condition that develops progressive hepatic degeneration through free radicals. OBJECTIVE: The present study was designed to extract and identify two flavonoids in Phlomoides hyoscyamoides plant, native to Iran and evaluate the role of quercetin identified on the liver injury among bile ductligated rats. METHODS: This study was conducted on 25 male Wistar rats within three groups of sham control, mere bile duct-ligated, and bile duct-ligated with quercetin. The bile duct-ligated animals received quercetin at a dose of 50 mg/kg/day for 10 days, followed by biochemical tests, oxidative stress markers, activity of antioxidant enzymes and hematoxylin and eosin staining. Molecular docking was used to explore the interactive behavior of quercetin with glutathione peroxidase. RESULTS: According to analyses of the obtained extract, two main active ingredients of P. hyoscyamoides were rutin and quercetin. Bile duct-ligated group showed a significant liver necrosis, a clear increase in plasma and tissue oxidative stress parameters, and a decrease in glutathione peroxidase activity as compared to sham control group. Quercetin injection in bile duct-ligated rats resulted in significant decrease in hydroxyproline, protein carbonyl and histopathologic indexes and significant increase in glutathione peroxidase activity (P-value≤0.05). Based on the molecular docking, the quercetin was able to regulate the glutathione peroxidase activity. CONCLUSION: The quercetin acts as an enzyme inducer by renewing the glutathione peroxidase activity and inhibiting the oxidation of proteins and hence decreases the oxidative stress. These results could be a sign of confirming the positive role of quercetin in attenuating the liver damage and degeneration.

Pharmacophore Modeling, Synthesis, Scaffold Hopping and Biological ß- Hematin Inhibition Interaction Studies for Anti-malaria Compounds.

Backgound: Exploring potent compounds is critical to generating multi-target drug discovery. Hematin crystallization is an important mechanism of malaria. METHODS: A series of chloroquine analogues were designed using a repositioning approach to develop new anticancer compounds. Protein-ligand interaction fingerprints and ADMET descriptors were used to assess docking performance in virtual screenings to design chloroquine hybrid ß-hematin inhibitors. A PLS algorithm was applied to correlate the molecular descriptors to IC50 values. The modeling presented excellent predictive power with correlation coefficients for calibration and cross-validation of r2 = 0.93 and q2 = 0.72. Using the model, a series of 4-aminoquinlin hybrids were synthesized and evaluated for their biological activity as an external test series. These compounds were evaluated for cytotoxic cell lines and ß-hematin inhibition. RESULTS: The target compounds exhibited high ß-hematin inhibition activity and were 3-9 times more active than the positive control. Furthermore, all the compounds exhibited moderate to high cytotoxic activity. The most potent compound in the dataset was docked with hemoglobin and its pharmacophore features were generated. These features were used as input to the Pharmit server for screening of six databases. CONCLUSION: The compound with the best score from ChEMBL was 2016904, previously reported as a VEGFR-2 inhibitor. The 11 compounds selected presented the best Gold scores with drug-like properties and can be used for drug development.

Ugi efficient synthesis, biological evaluation and molecular docking of coumarin-quinoline hybrids as apoptotic agents through mitochondria-related pathways.

Ugi reaction was a reliable procedure for the synthesis of new coumarin-quinoline frameworks. Excellent yields, mild reaction conditions and easily available and inexpensive starting materials are advantages of this protocol. Cytotoxic effects of fourteen products were investigated in A2780 human ovarian cancer cells. Two synthesized compounds (L11 and L12) exhibited more anti-cancer activity than other derivatives with IC50 values of 0.042 mmol/L and 0.102 mmol/L, respectively and were thus selected for further studies. Apoptosis was induced through the intrinsic pathway by activating caspase 9 and ended at the executioner pathway of caspase 3. Measurement of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were also carried out for both of them. Further studies on a mechanism by Real Time-PCR and Western blot analysis were performed for anti-apoptotic proteins Bcl-2 and survivin both in mRNA and protein level relating to the untreated A2780 cells. The treatment of A2780 cells with compound L11 significantly (P-value ≤ 0.05) induced apoptosis by down-regulation of Bcl-2 and survivin both in mRNA and protein level via a single dose (0.042 mmol/L), as well as activation of caspase 9 and 3, loss of MMP, and high ROS. Accordingly, findings supported the first report under which the pro-apoptotic activity of compound L11 as an apoptosis-inducing agent was related to mitochondrial-mediated dysfunction signaling pathways. Molecular docking supports experimental outcomes. Evidently, coumarin-quinoline scaffolds are potentially favorable options for further assessment as influential chemotherapeutic agents for the future.

Highly water-dispersible calcium lignosulfonate-capped MnO nanoparticles as a T 1 MRI contrast agent with exceptional colloidal stability, low toxicity and remarkable relaxivity.

A simple and efficient method to synthesize highly water-dispersible calcium lignosulfonate-coated manganese oxide nanoparticles as a potential candidate for the current magnetic resonance imaging (MRI) T 1 contrast agents was reported. Hydrophobic MnO nanoparticles with dimensions of about 10 nm were prepared by thermal decomposition of manganese(ii)acetylacetonate in the presence of oleic acid as a surfactant. The characteristics of the synthesized nanoparticles, cytotoxicity assay and in vitro MRI properties were investigated in detail. Results showed that calcium lignosulfonate has a great influence on the colloidal stability and biocompatibility of MnO nanoparticles in water. Furthermore, this coating agent ensures abundant exposure of external Mn ion with protons of water, which endows the nanoparticles with a longitudinal molar relaxivity (r 1) of 4.62 mM-1 s-1. An efficient contrast enhancement effect was observed in the study of MRI investigations.

Synthesis of some new triamide derivatives via Ugi five-component reaction in aqueous solution.

Triamide derivatives have been synthesized in good yields in a novel, one-pot, five-component, and efficient process by the reaction of Z-oxazolone, water, primary amines, aldehydes, isocyanides, in the presence of catalytic amount of KAl(SO4)2·12H2O (alum) as a non-toxic, reusable, inexpensive, and easily available reagent via Ugi reaction in aqueous solution.

NMR spectroscopy-based metabolomic study of serum in sulfur mustard exposed patients with lung disease.

Sulfur mustard (SM) is a vesication chemical warfare agent for which there is currently no antidote. Despite years of research, there is no common consensus about the pathophysiological basis of chronic pulmonary disease caused by this chemical warfare agent. In this study, we combined chemometric techniques with nuclear magnetic resonance (NMR) spectroscopy to explore the metabolic profile of sera from SM-exposed patients. A total of 29 serum samples obtained from 17 SM-injured patients, and 12 healthy controls were analyzed by Random Forest. Increased concentrations of seven amino acids, glycerol, dimethylamine, ketone bodies, lactate, acetate, citrulline and creatine together with the decreased very low-density lipoproteins (VLDL) levels were observed in patients compared with control subjects. Our study reveals the metabolic profile of sera from SM-injured patients and indicates that NMR-based methods can distinguish these patients from healthy controls.

NMR- and GC/MS-based metabolomics of sulfur mustard exposed individuals: a pilot study.

Sulfur mustard (SM) is a potent alkylating agent and its effects on cells and tissues are varied and complex. Due to limitations in the diagnostics of sulfur mustard exposed individuals (SMEIs) by noninvasive approaches, there is a great necessity to develop novel techniques and biomarkers for this condition. We present here the first nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC/MS) metabolic profiling of serum from and healthy controls to identify novel biomarkers in blood serum for better diagnostics. Of note, SMEIs were exposed to SM 30 years ago and that differences between two groups could still be found. Pathways in which differences between SMEIs and healthy controls are observed are related to lipid metabolism, ketogenesis, tricarboxylic acid (TCA) cycle and amino acid metabolism.

Pro-oxidant-antioxidant balance in Iranian veterans with sulfur mustard toxicity and different levels of pulmonary disorders.

OBJECTIVE: Sulfur mustard (SM) is a strong alkylating agent that primarily targets the skin, eye and lung. The current study evaluated the pro-oxidant-antioxidant balance (PAB) assay in human serum of SM-exposed patients. DESIGN AND METHODS: sera of 35 SM-exposed patients and 19 healthy volunteers were recruited. Both groups had nonsmoker and nonalcoholic people with no diseases such as diabetes, heart disease and other pulmonary diseases (COPD because of smoking, asthma and so on). All patients had documented exposure to SM. The PAB was measured. RESULTS: SM-exposed patients with normal values for pulmonary function test and severe obstructive pulmonary disease demonstrated a significant increase in PAB value in compared with healthy volunteers (the PAB values in healthy volunteers, normal and severe patients were 48.74 ± 21.07 HK, 101.45 ± 32.68 HK and 120.23 ± 31.55 HK, respectively). However, the level of oxidation is not related to the severity of disease defined by spirometry findings. A significant negative correlation was established between the PAB value and FEV1. CONCLUSIONS: The increased PAB value in chemical casualties showed that these patients are exposed to oxidative stress.

Sensitive determination of methadone in human serum and urine by dispersive liquid-liquid microextraction based on the solidification of a floating organic droplet followed by HPLC-UV.

Dispersive liquid-liquid microextraction based on solidification of floating organic droplet was developed for the extraction of methadone and determination by high-performance liquid chromatography with UV detection. In this method, no microsyringe or fiber is required to support the organic microdrop due to the usage of an organic solvent with a low density and appropriate melting point. Furthermore, the extractant droplet can be collected easily by solidifying it at low temperature. 1-Undecanol and methanol were chosen as extraction and disperser solvents, respectively. Parameters that influence extraction efficiency, i.e. volumes of extracting and dispersing solvents, pH, and salt effect, were optimized by using response surface methodology. Under optimal conditions, enrichment factor for methadone was 134 and 160 in serum and urine samples, respectively. The limit of detection was 3.34 ng/mmL in serum and 1.67 ng/mL in urine samples. Compared with the traditional dispersive liquid-liquid microextraction, the proposed method obtained lower limit of detection. Moreover, the solidification of floating organic solvent facilitated the phase transfer. And most importantly, it avoided using high-density and toxic solvents of traditional dispersive liquid-liquid microextraction method. The proposed method was successfully applied to the determination of methadone in serum and urine samples of an addicted individual under methadone therapy.

Sensitive determination of atorvastatin in human plasma by dispersive liquid-liquid microextraction and solidification of floating organic drop followed by high-performance liquid chromatography.

A novel and sensitive dispersive liquid-liquid microextraction method based on the solidification of the floating organic drop combined with high-performance liquid chromatography and ultraviolet detection was used for the determination of atorvastatine in blood serum samples. The chromatographic separation of atorvastatin was carried out using methanol as the mobile phase organic modifier. Various parameters affecting the extraction efficiency were optimized, such as the kind and volume of extraction solvent (1-undecanol) and disperser solvent (acetonitrile), pH, and the extraction time. The calibration curve was linear in the range of 0.2-6000 µg/L of atorvastatin (r(2) = 0.995) with a limit of detection of 0.07 µg/L. The relative standard deviation for 100 µg/L of atorvastatin in human plasma was 8.4% (n = 4). The recoveries of plasma samples spiked with atorvastatin were in the range of 98.8-113.8%. The obtained results showed that the proposed method is fast, simple, and reliable for the determination of very low concentrations of atorvastatin in human plasma samples.