One-Pot Microwave Synthesis of Pyrimido[4,5-b]quinoline and its C- and S-Glycosides with Anti-Inflammatory and Anticancer Activities

An efficient one-pot synthesis of 2-thioxopyrimido[4,5-b]quinoline 3a,b has been accomplished from a three-component reaction of 6-aminothiouracil, cyclohexanone and aromatic aldehyde under microwave irradiation. Compound 3a,b was used as a key intermediate for the synthesis of S- and C-nucleoside analogs of types, 5-(4-fluorophenyl / 4-anisyl)-2-S-(β-D-ribofuranosyl / arabinofuranosyl)-6,7,8,9-tetrahydro-3H-pyrimido[4,5-b]quinolin-4-one (6a–d) and 5-(4-fluorophenyl / 4-anisyl)-2-S-(β-D-gluco / galactopyranosyl)-6,7,8,9-tetrahydro-3H-pyrimido[4,5-b]quinolin-4-one (8a–d). Also. the 2-hydrazino compounds 9a,b were used for the synthesis of 3-(glycosyl)-6-(4-substituted phenyl)-7,8,9,10-tetrahydro[1,2,4]triazolo[4\u27,3\u27:1,2]pyrimido[4,5-b]quinoline-5-(1H)-one (11a–d and 13a–d). The title compounds were investigated for anti-inflammatory and anticancer activities. Compounds 11a exhibited the comparable anti-inflammatory activity (83.4 %) to the standard drug Indomethacin (85.2 %). 5-(4-Fluorophenyl)-2-S-(β-D-ribofuranosyl)-6,7,8,9-tetrahydro-3H-pyrimido[4,5-b]quinolin-4-one 6a and 3-(ribosyl)-5-(4-fluorophenyl)-7,8,9,10-tetrahydro[1,2,4]triazolo[4\u27,3\u27:1,2]pyrimido[4,5-b]quinolin-5-one (13a) exhibited the maximum cytotoxic effect against the three human cancer cell lines with inhibitory effects higher than the reference doxorubicin. This work is licensed under a Creative Commons Attribution 4.0 International License

Thromboembolism in inflammatory bowel diseases: a report from Saudi Arabia

Thromboembolism (TE) is a serious but under-recognized complication of inflammatory bowel disease (IBD). This is specially so in developing countries where the incidence of IBD is low. In Saudi Arabia, IBD is considered to be rare, but the incidence is increasing. Where the clinical manifestations resemble those of developed countries, TE as a complication of IBD is considered to be very rare. This report describes six IBD patients with TE. This importance of the complication of TE is stressed, and physicians caring for these patients should be aware of it in order to obviate potential morbidity and mortality

Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity

Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful to identify crucial pharmacophoric features. The present work is based on a larger data set comprising 1121 diverse compounds to develop a QSAR model having a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The developed six parametric model fulfils the recommended values for internal and external validation along with Y-randomization parameters such as R2tr = 0.831, Q2LMO = 0.828, R2ex = 0.783. The present analysis reveals that anti-thrombotic activity is found to be correlated with concealed structural traits such as positively charged ring carbon atoms, specific combination of aromatic Nitrogen and sp2-hybridized carbon atoms, etc. Thus, the model captured reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with factor Xa. The analysis led to the identification of useful novel pharmacophoric features, which could be used for future optimization of lead compounds

Application of codon usage and context analysis in genes up- or down-regulated in neurodegeneration and cancer to combat comorbidities

IntroductionNeurodegeneration and cancer present in comorbidities with inverse effects due to the expression of genes and pathways acting in opposition. Identifying and studying the genes simultaneously up or downregulated during morbidities helps curb both ailments together.MethodsThis study examines four genes. Three of these (Amyloid Beta Precursor Protein (APP), Cyclin D1 (CCND1), and Cyclin E2 (CCNE2) are upregulated, and one protein phosphatase 2 phosphatase activator (PTPA) is simultaneously downregulated in both disorders. We investigated molecular patterns, codon usage, codon usage bias, nucleotide bias in the third codon position, preferred codons, preferred codon pairs, rare codons, and codon context.ResultsParity analysis revealed that T is preferred over A, and G is preferred over C in the third codon position, suggesting composition plays no role in nucleotide bias in both the upregulated and downregulated gene sets and that mutational forces are stronger in upregulated gene sets than in downregulated ones. Transcript length influenced the overall %A composition and codon bias, and the codon AGG exerted the strongest influence on codon usage in both the upregulated and downregulated gene sets. Codons ending in G/C were preferred for 16 amino acids, and glutamic acid-, aspartic acid-, leucine-, valine-, and phenylalanine-initiated codon pairs were preferred in all genes. Codons CTA (Leu), GTA (Val), CAA (Gln), and CGT (Arg) were underrepresented in all examined genes.DiscussionUsing advanced gene editing tools such as CRISPR/Cas or any other gene augmentation technique, these recoded genes may be introduced into the human body to optimize gene expression levels to augment neurodegeneration and cancer therapeutic regimens simultaneously

A Combined Use of Rhizobacteria and Moringa Leaf Extract Mitigates the Adverse Effects of Drought Stress in Wheat (Triticum aestivum L.)

Less nutrient availability and drought stress are some serious concerns of agriculture. Both biotic and abiotic stress factors have the potential to limit crop productivity. However, several organic extracts obtained from moringa leaves may induce immunity in plants under nutritional and drought stress for increasing their survival. Additionally, some rhizobacterial strains have the ability to enhance root growth for better nutrient and water uptake in stress conditions. To cover the knowledge gap on the interactive effects of beneficial rhizobacteria and moringa leaf extracts (MLEs), this study was conducted. The aim of this experimental study was to investigate the effectiveness of sole and combined use of rhizobacteria and MLEs against nutritional and drought stress in wheat. Nitrogen-fixing bacteria Pseudomonas aeruginosa (Pa) (10(8) CFU ml(-1)) was inoculated to wheat plants with and without foliar-applied MLEs at two different concentrations (MLE 1 = 1:15 v/v and MLE 2 = 1:30 v/v) twice at 25 and 35 days after seed sowing (50 ml per plant) after the establishment of drought stress. Results revealed that Pa + MLE 2 significantly increased fresh weight (FW), dry weight (DW), lengths of roots and shoot and photosynthetic contents of wheat. A significant enhancement in total soluble sugars, total soluble proteins, calcium, potassium, phosphate, and nitrate contents validated the efficacious effect of Pa + MLE 2 over control-treated plants. Significant decrease in sodium, proline, glycine betaine, electrolyte leakage, malondialdehyde, hydrogen peroxide, superoxide dismutase (SOD), and peroxide (POD) concentrations in wheat cultivated under drought stress conditions also represents the imperative role of Pa + MLE 2 over control. In conclusion, Pa + MLE 2 can alleviate nutritional stress and drought effects in wheat. More research in this field is required to proclaim Pa + MLE 2 as the most effective amendment against drought stress in distinct agroecological zones, different soil types, and contrasting wheat cultivars worldwide.Peer reviewe

In-silico studies to recognize repurposing therapeutics toward arginase-I inhibitors as a potential onco-immunomodulators

Rudolf Virchow was the first person to point out the important link between immune function and cancer. He did this by noticing that leukocytes were often found in tumors. Overexpression of arginase 1 (ARG1) and inducible nitric oxide synthase (iNOS) in myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) depletes both intracellular and extracellular arginine. TCR signalling is slowed as a result, and the same types of cells produce reactive oxygen and nitrogen species (ROS and RNS), which aggravates the situation. Human arginase I is a double-stranded manganese metalloenzyme that helps L-arginine break down into L-ornithine and urea. Thus, a quantitative structure-activity relationship (QSAR) analysis was performed to unearth the unrecognised structural aspects crucial for arginase-I inhibition. In this work, a balanced QSAR model with good prediction performance and clear mechanistic interpretation was developed using a dataset of 149 molecules encompassing a broad range of structural scaffolds and compositions. The model was made to meet OECD standards, and all of its validation parameters have values that are higher than the minimum requirements (R2tr = 0.89, Q2LMO = 0.86, and R2ex = 0.85). The present QSAR study linked structural factors to arginase-I inhibitory action, including the proximity of lipophilic atoms to the molecule’s centre of mass (within 3A), the position of the donor to the ring nitrogen (exactly 3 bonds away), and the surface area ratio. As OAT-1746 and two others are the only arginase-I inhibitors in development at the time, we have performed a QSAR-based virtual screening with 1650 FDA compounds taken from the zinc database. In this screening, 112 potential hit compounds were found to have a PIC50 value of less than 10 nm against the arginase-I receptor. The created QSAR model’s application domain was evaluated in relation to the most active hit molecules identified using QSAR-based virtual screening, utilising a training set of 149 compounds and a prediction set of 112 hit molecules. As shown in the Williams plot, the top hit molecule, ZINC000252286875, has a low leverage value of HAT i/i h* = 0.140, placing it towards the boundary of the usable range. Furthermore, one of 112 hit molecules with a docking score of −10.891 kcal/mol (PIC50 = 10.023 M) was isolated from a study of arginase-I using molecular docking. Protonated ZINC000252286875-linked arginase-1 showed 2.9 RMSD, whereas non-protonated had 1.8. RMSD plots illustrate protein stability in protonated and non-protonated ZINC000252286875-bound states. Protonated-ZINC000252286875-bound proteins contain 25 Rg. The non-protonated protein-ligand combination exhibits a 25.2-Rg, indicating compactness. Protonated and non-protonated ZINC000252286875 stabilised protein targets in binding cavities posthumously. Significant root mean square fluctuations (RMSF) were seen in the arginase-1 protein at a small number of residues for a time function of 500 ns in both the protonated and unprotonated states. Protonated and non-protonated ligands interacted with proteins throughout the simulation. ZINC000252286875 bound Lys64, Asp124, Ala171, Arg222, Asp232, and Gly250. Aspartic acid residue 232 exhibited 200% ionic contact. 500-ns simulations-maintained ions. Salt bridges for ZINC000252286875 aided docking. ZINC000252286875 created six ionic bonds with Lys68, Asp117, His126, Ala171, Lys224, and Asp232 residues. Asp117, His126, and Lys224 showed 200% ionic interactions. In protonated and deprotonated states, GbindvdW, GbindLipo, and GbindCoulomb energies played crucial role. Moreover, ZINC000252286875 meets all of the ADMET standards to serve as a drug. As a result, the current analyses were successful in locating a novel and potent hit molecule that inhibits arginase-I effectively at nanomolar concentrations. The results of this investigation can be used to develop brand-new arginase I inhibitors as an alternative immune-modulating cancer therapy

ВЛИЯНИЕ ВЛАЖНОСТИ И СОЛЕЙ НА ПРОЧНОСТНЫЕ И ДЕФОРМАЦИОННЫЕ СВОЙСТВА ДИСПЕРСНЫХ ГРУНТОВ

Investigations of changes in strength and deformation properties of disperse soil have been carried under laboratory conditions. The paper proves salt influence on changes of their propertiesПроведены исследования процессов изменения прочностных и деформационных свойств дисперсных грунтов в лабораторных условиях. Доказано влияние солей на изменение этих свойств

Target specific inhibition of West Nile virus envelope glycoprotein and methyltransferase using phytocompounds: an in silico strategy leveraging molecular docking and dynamics simulation

Mosquitoes are the primary vector for West Nile virus, a flavivirus. The virus’s ability to infiltrate and establish itself in increasing numbers of nations has made it a persistent threat to public health worldwide. Despite the widespread occurrence of this potentially fatal disease, no effective treatment options are currently on the market. As a result, there is an immediate need for the research and development of novel pharmaceuticals. To begin, molecular docking was performed on two possible West Nile virus target proteins using a panel of twelve natural chemicals, including Apigenin, Resveratrol, Hesperetin, Fungisterol, Lucidone, Ganoderic acid, Curcumin, Kaempferol, Cholic acid, Chlorogenic acid, Pinocembrin, and Sanguinarine. West Nile virus methyltransferase (PDB ID: 2OY0) binding affinities varied from −7.4 to −8.3 kcal/mol, whereas West Nile virus envelope glycoprotein affinities ranged from −6.2 to −8.1 kcal/mol (PDB ID: 2I69). Second, substances with larger molecular weights are less likely to be unhappy with the Lipinski rule. Hence, additional research was carried out without regard to molecular weight. In addition, compounds 01, 02, 03, 05, 06, 07, 08, 09, 10 and 11 are more soluble in water than compound 04 is. Besides, based on maximum binding affinity, best three compounds (Apigenin, Curcumin, and Ganoderic Acid) has been carried out molecular dynamic simulation (MDs) at 100 ns to determine their stability. The MDs data is also reported that these mentioned molecules are highly stable. Finally, advanced principal component analysis (PCA), dynamics cross-correlation matrices (DCCM) analysis, binding free energy and dynamic cross correlation matrix (DCCM) theoretical study is also included to established mentioned phytochemical as a potential drug candidate. Research has indicated that the aforementioned natural substances may be an effective tool in the battle against the dangerous West Nile virus. This study aims to locate a bioactive natural component that might be used as a pharmaceutical

TCRep 3D: An Automated In Silico Approach to Study the Structural Properties of TCR Repertoires

TCRep 3D is an automated systematic approach for TCR-peptide-MHC class I structure prediction, based on homology and ab initio modeling. It has been considerably generalized from former studies to be applicable to large repertoires of TCR. First, the location of the complementary determining regions of the target sequences are automatically identified by a sequence alignment strategy against a database of TCR Vα and Vβ chains. A structure-based alignment ensures automated identification of CDR3 loops. The CDR are then modeled in the environment of the complex, in an ab initio approach based on a simulated annealing protocol. During this step, dihedral restraints are applied to drive the CDR1 and CDR2 loops towards their canonical conformations, described by Al-Lazikani et. al. We developed a new automated algorithm that determines additional restraints to iteratively converge towards TCR conformations making frequent hydrogen bonds with the pMHC. We demonstrated that our approach outperforms popular scoring methods (Anolea, Dope and Modeller) in predicting relevant CDR conformations. Finally, this modeling approach has been successfully applied to experimentally determined sequences of TCR that recognize the NY-ESO-1 cancer testis antigen. This analysis revealed a mechanism of selection of TCR through the presence of a single conserved amino acid in all CDR3β sequences. The important structural modifications predicted in silico and the associated dramatic loss of experimental binding affinity upon mutation of this amino acid show the good correspondence between the predicted structures and their biological activities. To our knowledge, this is the first systematic approach that was developed for large TCR repertoire structural modeling