Synthesis, biochemical characterization and in silico investigation of 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid derivatives: dual action mode inhibitors of urease and virulent bacterial stains.

In the present work, we reported the synthesis of Schiff bases from 4-phenoxy-5-sulfamoylbenzoic acid motif. The reaction was carried out by substitution of different aldehyde and ketones at sulfamoyl group of sulfamoylbenzoic acid. The generated substituted products (4a-4i) possessed potent structure activity relationship and exhibited drug like properties. The structures of synthesized compounds were characterized on the basis of FT-IR, 1H NMR, 13C NMR and mass spectroscopic data. The effects of synthesized products were investigated on urease enzyme through anti-urease enzyme inhibition assay (Weather burn method). These compounds were further evaluated for antibacterial potential. The Rationale behind the assessment of antibacterial activity was to investigate the synthesized compound's dual mode action against urease and virulent bacterial strains in order to develop a lead candidate for the treatment of GIT diseases such as gastric and peptic ulcers, as well as hepatic encephalopathy. The synthesized derivatives have outstanding anti-urease and antibacterial action, as is evident from in vitro and in silico studies. As a result, these compounds (3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid; 4a-4i) might be explored further as a potential lead for the development of potent inhibitors in the future.

Robust Epileptic Seizure Detection Using Long Short-Term Memory and Feature Fusion of Compressed Time-Frequency EEG Images.

Epilepsy is a prevalent neurological disorder with considerable risks, including physical impairment and irreversible brain damage from seizures. Given these challenges, the urgency for prompt and accurate seizure detection cannot be overstated. Traditionally, experts have relied on manual EEG signal analyses for seizure detection, which is labor-intensive and prone to human error. Recognizing this limitation, the rise in deep learning methods has been heralded as a promising avenue, offering more refined diagnostic precision. On the other hand, the prevailing challenge in many models is their constrained emphasis on specific domains, potentially diminishing their robustness and precision in complex real-world environments. This paper presents a novel model that seamlessly integrates the salient features from the time-frequency domain along with pivotal statistical attributes derived from EEG signals. This fusion process involves the integration of essential statistics, including the mean, median, and variance, combined with the rich data from compressed time-frequency (CWT) images processed using autoencoders. This multidimensional feature set provides a robust foundation for subsequent analytic steps. A long short-term memory (LSTM) network, meticulously optimized for the renowned Bonn Epilepsy dataset, was used to enhance the capability of the proposed model. Preliminary evaluations underscore the prowess of the proposed model: a remarkable 100% accuracy in most of the binary classifications, exceeding 95% accuracy in three-class and four-class challenges, and a commendable rate, exceeding 93.5% for the five-class classification.

Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family.

Mitochondrial protein synthesis requires three elongation factors including EF-Tu (TUFM; OMIM 602389), EF-Ts (TSFM; OMIM 604723), and EF-G1 (GFM1; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in GFM1 located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G > A; p.Val137Met) and paternal (NM_001308164.1:c.1880G > A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as "likely-pathogenic" according to the recommendation of ACMG/AMP guideline. GFM1 alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10-17 years, without developing any life-threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical-by-descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of GFM1 gene.

Prospect of Anterior Gradient 2 homodimer inhibition via repurposing FDA-approved drugs using structure-based virtual screening.

Anterior Gradient 2 (AGR2) has recently been reported as a tumor biomarker in various cancers, i.e., breast, prostate and lung cancer. Predominantly, AGR2 exists as a homodimer via a dimerization domain (E60-K64); after it is self-dimerized, it helps FGF2 and VEGF to homo-dimerize and promotes the angiogenesis and the invasion of vascular endothelial cells and fibroblasts. Up till now, no small molecule has been discovered to inhibit the AGR2-AGR2 homodimer. Therefore, the present study was performed to prepare a validated 3D structure of AGR2 by homology modeling and discover a small molecule by screening the FDA-approved drugs library on AGR2 homodimer as a target protein. Thirteen different homology models of AGR2 were generated based on different templates which were narrowed down to 5 quality models sorted by their overall Z-scores. The top homology model based on PDB ID = 3PH9 was selected having the best Z-score and was further assessed by Verify-3D, ERRAT and RAMPAGE analysis. Structure-based virtual screening narrowed down the large library of FDA-approved drugs to ten potential AGR2-AGR2 homodimer inhibitors having FRED score lower than - 7.8 kcal/mol in which the top 5 drugs' binding stability was counter-validated by molecular dynamic simulation. To sum up, the present study prepared a validated 3D structure of AGR2 and, for the first time reported the discovery of 5 FDA-approved drugs to inhibit AGR2-AGR2 homodimer by using structure-based virtual screening. Moreover, the binding of the top 5 hits with AGR2 was also validated by molecular dynamic simulation. A validated 3D structure of Anterior Gradient 2 (AGR2) was prepared by homology modeling, which was used in virtual screening of FDA-approved drugs library for the discovery of prospective inhibitors of AGR2-AGR2 homodimer.

Synthesis of novel hybrid pharmacophore of N-((4-sulfamoylphenyl)carbamothioyl)alkanamides as potent carbonic anhydrase-II and 15-lipoxygenase inhibitors.

A series of N-((4-sulfamoylphenyl)carbamothioyl)alkanamides (5a-j) were synthesized by the reaction of sulphanilamide in dry acetone with freshly prepared alkyl and acyl isothiocyanates (5a-j). The structures of products were confirmed by IR, 1 H, and 13 C NMR. The synthesized compounds were screened as inhibitors of the bovine erythrocyte carbonic anhydrase isoform II (bCA II) and 15-lipoxygenase enzyme (15-LOX). Most of the derivatives showed significant activity against bCA-II while only few compounds were found active against 15-LOX. Molecular docking studies of most active compounds were carried out against bCA II as well as 15-LOX to rationalize the binding mode and interactions of compound in the active sites. Additionally, the pharmacokinetic properties of the compounds were predicted through computational tools, which reflect that these compounds possess acceptable pharmacokinetic profile and good drug-likeness.

Chemical Composition, Biological Activities and In Silico Analysis of Essential Oils of Three Endemic Prangos Species from Turkey.

In this study, the essential oils (EOs) obtained from three endemic Prangos species from Turkey (P. heyniae, P. meliocarpoides var. meliocarpoides, and P. uechtritzii) were studied for their chemical composition and biological activities. ß-Bisabolenal (12.2%) and caryophyllene oxide (7.9%) were the principal components of P. heyniae EO, while P. meliocarpoides EO contained sabinene (16.7%) and p-cymene (13.2%), and P. uechtritzii EO contained p-cymene (24.6%) and caryophyllene oxide (19.6%), as the most abundant components. With regard to their antioxidant activity, all the EOs were found to possess free radical scavenging potential demonstrated in both DPPH and ABTS assays (0.43-1.74 mg TE/g and 24.18-92.99 mg TE/g, respectively). Additionally, while no inhibitory activity was displayed by P. meliocarpoides and P. uechtritzii EOs against both cholinesterases (acetyl- and butyryl-cholinesterases). Moreover, all the EOs were found to act as inhibitors of tyrosinase (46.34-69.56 mg KAE/g). Molecular docking revealed elemol and α-bisabolol to have the most effective binding affinity with tyrosinase and amylase. Altogether, this study unveiled some interesting biological activities of these EOs, especially as natural antioxidants and tyrosinase inhibitors and hence offers stimulating prospects of them in the development of anti-hyperpigmentation topical formulations.

Anti-Inflammatory and Anti-Rheumatic Potential of Selective Plant Compounds by Targeting TLR-4/AP-1 Signaling: A Comprehensive Molecular Docking and Simulation Approaches.

Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydrophobic interactions. With TLR-4, rutin had the highest binding energy (-10.4 kcal/mol), poncirin had the highest binding energy (-9.4 kcal/mol) with NF-κB and JNK (-9.5 kcal/mol), respectively, and icariin had the highest binding affinity (-9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin's greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simulation, and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maximum toxic dose. Moreover, the blood-brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited promising physico-chemical as well as drug-likeness properties. Consequently, these selected compounds portray promising anti-inflammatory and drug-likeness properties.

Small organic molecules accelerate the expansion of regulatory T cells.

The regulatory T cells (Treg cells) expressing CD4 + CD25 + FOXP3 + markers are indispensable for the initiation of immune homeostasis and tolerance to self-antigens in both mice and humans. A decrease in regulatory T cells leads to various autoimmune pathologies. Herein, we report three low molecular weight, small organic molecules as a new series of Treg proliferators TRP-1-3. These small molecules were tested for their proliferative effect on regulatory T cells. It was found that TRP-1 (Oleracein E) strongly accelerates the Treg proliferation in vitro in a concentration-dependent manner. The effect was evident for all subsets of Treg cells tested, including naturally occurring, thymus-derived and peripherally-induced or adaptive Treg, indicating an effect independent of the maturation site. Importantly, increased Treg cells numbers by TRP-1 correlated with improved CD4 + CD25 + FOXP3 + expression in vitro, while propidium iodide-based staining showed low TRP-1-induced cytotoxicity. Molecular docking plus simulation studies of these TRP-1-3 with IL-2R, mTOR and TCR receptors suggest a TCR-based Treg cells activation mechanism. Because of its high Treg cells activities and low cellular cytotoxicity, TRP-1-3 may be useful in stimulating ex-vivo/in-vivo, Treg cell-specific responses for therapeutic applications.

Isolation, Structure Elucidation and In Silico Prediction of Potential Drug-Like Flavonoids from Onosma chitralicum Targeted towards Functionally Important Proteins of Drug-Resistant Bad Bugs.

Admittedly, the disastrous emergence of drug resistance in prokaryotic and eukaryotic human pathogens has created an urgent need to develop novel chemotherapeutic agents. Onosma chitralicum is a source of traditional medicine with cooling, laxative, and anthelmintic effects. The objective of the current research was to analyze the biological potential of Onosma chitralicum, and to isolate and characterize the chemical constituents of the plant. The crude extracts of the plant prepared with different solvents, such as aqueous, hexane, chloroform, ethyl acetate, and butanol, were subjected to antimicrobial activities. Results corroborate that crude (methanol), EtoAc, and n-C6H14 fractions were more active against bacterial strains. Among these fractions, the EtoAc fraction was found more potent. The EtoAc fraction was the most active against the selected microbes, which was subjected to successive column chromatography, and the resultant compounds 1 to 7 were isolated. Different techniques, such as UV, IR, and NMR, were used to characterize the structures of the isolated compounds 1-7. All the isolated pure compounds (1-7) were tested for their antimicrobial potential. Compounds 1 (4',8-dimethoxy-7-hydroxyisoflavone), 6 (5,3',3-trihydroxy-7,4'-dimethoxyflavanone), and 7 (5',7,8-trihydroxy-6,3',4'-trimethoxyflavanone) were found to be more active against Staphylococcus aureus and Salmonella Typhi. Compound 1 inhibited S. typhi and S. aureus to 10 ± 0.21 mm and 10 ± 0.45 mm, whereas compound 6 showed inhibition to 10 ± 0.77 mm and 9 ± 0.20 mm, respectively. Compound 7 inhibited S. aureus to 6 ± 0.36 mm. Compounds 6 and 7 showed significant antibacterial potential, and the structure-activity relationship also justifies their binding to the bacterial enzymes, i.e., beta-hydroxyacyl dehydratase (HadAB complex) and tyrosyl-tRNA synthetase. Both bacterial enzymes are potential drug targets. Further, the isolated compounds were found to be active against the tested fungal strains. Whereas docking identified compound 7, the best binder to the lanosterol 14α-demethylase (an essential fungal cell membrane synthesizing enzyme), reported as an antifungal fluconazole binding enzyme. Based on our isolation-linked preliminary structure-activity relationship (SAR) data, we conclude that O. chitralicum can be a good source of natural compounds for drug development against some potential enzyme targets.

Counteracting the Ramifications of UVB Irradiation and Photoaging with Swietenia macrophylla King Seed.

In this day and age, the expectation of cosmetic products to effectively slow down skin photoaging is constantly increasing. However, the detrimental effects of UVB on the skin are not easy to tackle as UVB dysregulates a wide range of molecular changes on the cellular level. In our research, irradiated keratinocyte cells not only experienced a compromise in their redox system, but processes from RNA translation to protein synthesis and folding were also affected. Aside from this, proteins involved in various other processes like DNA repair and maintenance, glycolysis, cell growth, proliferation, and migration were affected while the cells approached imminent cell death. Additionally, the collagen degradation pathway was also activated by UVB irradiation through the upregulation of inflammatory and collagen degrading markers. Nevertheless, with the treatment of Swietenia macrophylla (S. macrophylla) seed extract and fractions, the dysregulation of many genes and proteins by UVB was reversed. The reversal effects were particularly promising with the S. macrophylla hexane fraction (SMHF) and S. macrophylla ethyl acetate fraction (SMEAF). SMHF was able to oppose the detrimental effects of UVB in several different processes such as the redox system, DNA repair and maintenance, RNA transcription to translation, protein maintenance and synthesis, cell growth, migration and proliferation, and cell glycolysis, while SMEAF successfully suppressed markers related to skin inflammation, collagen degradation, and cell apoptosis. Thus, in summary, our research not only provided a deeper insight into the molecular changes within irradiated keratinocytes, but also serves as a model platform for future cosmetic research to build upon. Subsequently, both SMHF and SMEAF also displayed potential photoprotective properties that warrant further fractionation and in vivo clinical trials to investigate and obtain potential novel bioactive compounds against photoaging.

Adverse drug event of hypokalaemia-induced cardiotoxicity secondary to the use of laxatives: A systematic review of case reports.

WHAT IS KNOWN AND OBJECTIVE: The imbalance in serum potassium caused by laxatives can negatively affect the cardiovascular system, leading to life-threatening consequences. Our objective was to evaluate the reported evidence of adverse events related to the cardiac system due to laxative-induced hypokalaemia from case reports. METHODS: A systematic electronic literature search of PubMed, Embase, the Cochrane Library and Science Direct was conducted for the period 1995-2019. In these databases, search terms describing hypokalaemia and cardiotoxicity were combined with the term laxative use. RESULTS AND DISCUSSION: Over the 23 years, 27 incidents were identified in 12 countries. There were 19 female and eight male patients, with ages ranging from 1 month to 93 years. The frequency of reported cases according to severity was the following: severe hypokalaemia 48%, moderate hypokalaemia 44.4% and mild hypokalaemia 7.4%. In 70% of patients, the effect of laxative on the heart was typical hypokalaemic electrographic changes, 7.4% showed abnormal changes in cardiac rhythm, whereas in 18.5%, the cardiotoxicity observed was a very serious kind. Two patients died due to severe cardiac effects. WHAT IS NEW AND CONCLUSION: The laxatives-along with the involvement of some other contributing factors-caused mild-to-severe hypokalaemic cardiotoxicity. These factors were non-adherence of the patient to the recommended dosage, laxative abuse, drug-drug and drug-disease interactions, non-potassium electrolyte imbalances and the use of herbal laxatives. We recommend that laxatives and aggravating factors should be taken into account in the assessment of patients with suspected hypokalaemic cardiotoxicity.

UHPLC-MS phytochemical profiling, biological propensities and in-silico studies of Alhagi maurorum roots: a medicinal herb with multifunctional properties.

The biological, chemical, and in silico properties of methanol and dichloromethane (DCM) extracts of Alhagi maurorum roots with respect to the antioxidant, enzyme inhibition, and phytochemical composition were evaluated. Total bioactive contents were determined spectrophotometrically, and the individual secondary metabolites composition was assessed via ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) analysis. Antioxidant capacities were evaluated using a panoply of assays (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radical scavenging, ferric reducing antioxidant power (FRAP), cupric reducing antioxidant power (CUPRAC), phosphomolybdenum total antioxidant capacity (TAC), and metal chelating activity (MCA)). The enzyme inhibition potential was studied against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-amylase, α-glucosidase, tyrosinase, urease and lipoxygenase (LOX) enzymes. The methanol extract was found to contain higher total phenolic (105.91 mg GAE/g extract) and flavonoid (2.27 mg RE/g extract) contents which can be correlated to its more substantial antioxidant potential as well as AChE, BChE, tyrosinase and α-glucosidase inhibition. However, the DCM extract was the most effective against α-amylase (1.86 mmol ACAE/g extract) enzyme inhibition. The UHPLC-MS analysis of methanol extract identified the tentative presence of a total of 18 secondary metabolites, including flavonoids, saponins, phenolic and terpenoid derivatives. Three compounds named emmotin A, luteolin 5,3'-dimethyl ether, and preferrugone were further investigated for their in silico molecular docking studies against the tested enzymes. The selected compounds were found to have higher binding interaction with AChE followed by BChE, α-glucosidase, α-amylase, and tyrosinase. The results of the present study have demonstrated A. mauroram to be considered as a lead source of natural antioxidant and enzyme inhibitor compounds.

Xanthenone-based hydrazones as potent α-glucosidase inhibitors: Synthesis, solid state self-assembly and in silico studies.

Xanthenone based hydrazone derivatives (5a-n) have been synthesized as potential α-glucosidase inhibitors. All synthesized compounds (5a-n) are characterized by their FTIR, 1H NMR, 13C NMR and HRMS, and in case of 5g also by X-ray crystallographic technique. The compounds unveiled a varying degree of α-glucosidase inhibitory activity when compared with standard acarbose (IC50 = 375.38 ±â€¯0.12 µM). Amongst the series, compound 5l (IC50 = 62.25 ±â€¯0.11 µM) bearing a trifluoromethyl phenyl group is found to be the most active compound. Molecular modelling is performed to establish the binding pattern of the more active compound 5l, which revealed the significance of substitution pattern. The pharmacological properties of molecules are also calculated by MedChem Designer which determines the ADME (absorption, distribution, metabolism, excretion) properties of molecules. The solid state self-assembly of compound 5g is discussed to show the conformation and role of iminoamide moiety in the molecular packing.

The effect of some missing teeth on a subjects' oral health related quality of life.

OBJECTIVES: To determine the impact of missing teeth on the level of Oral Health Related Quality of Life (OHRQoL)in subjects reporting at a teaching dental hospital. METHOD: Using a structured Performa incorporating the 12-item General Oral Health Assessment Index (GOHAI) Questionnaire, and a consecutive (non-probability) sampling technique, data relating to 182 subjects fulfilling the study inclusion and exclusion criteria were collected using the method of interview and examination. Subjects responses to each of the 12 items of the GOHAI questionnaire were recorded to determine the impact of missing teeth on OHRQoL. Each of the GOHAI item had a maximum score of 5 thus giving a total of 60 as the maximum score. A high score of GOHAI indicated better ORHRQoL. The ORHRQol of subject was taken as good when the GOHAI score ranged 57-60, average when 51-56 and poor when ≤50. RESULTS: Subjects had a mean age of 35.6 ± 5.8 (S. Dev) with males as 50.5% compared to females (49.5%). The mean GOHAI score for all the subjects was 48.4 ± 8.2 as compared to the mean GOHAI score of 48.4 ± 8.2 for males and 47.6 ± 8.3 for females. The ORHRQoL was good in only 27%. A high proportion of subjects (53%) had poor OHRQoL. The number and the frontal location of the missing teeth adversely impacted OHRQoL. Missing maxillary anterior teeth had the most negative effect on OHRQoL. Missing mandibular first molar was the most common missing tooth either alone or in combination with other missing teeth among the subjects studied. The most important GOHAI items contributing to the adverse impact on the OHRQoL of the majority of subjects with some missing teeth were;often worried/concerned about dental problems and never having been pleased or happy with the look of their teeth and gum. CONCLUSION: The adverse effect of missing teeth on OHRQoL was substantial necessitating the importance of preventing the condition of missing teeth or restoring when missing and maintaining the oral health of subjects.

Substituted (E)-2-(2-benzylidenehydrazinyl)-4-methylthiazole-5-carboxylates as dual inhibitors of 15-lipoxygenase & carbonic anhydrase II: synthesis, biochemical evaluation and docking studies.

15-Lipoxygenase (15-LOX) plays a major role in many inflammatory lung diseases including chronic obstructive pulmonary disease (COPD), asthma and chronic bronchitis. Over-expression of 15-LOX is related with some specific carcinomas including pancreatic, gastric and brain tumor. Similarly among different isozymes of carbonic anhydrase (CA), CA II is expressed in pancreatic, gastric carcinomas as well as in brain tumors. Therefore, novel potent inhibitors of both 15-LOX and CA II are required to explore the role of these enzymes further and to enable the drug discovery efforts. For this purpose, a series of benzyledinyl-hydrazinyl substituted thiazole derivatives were designed, synthesized and characterized by FTIR, 1H, &13C NMR spectroscopy. The derivatives were then evaluated for their potential to inhibit 15-LOX and bovine carbonic anhydrase II (bCA II). Most of these compounds showed excellent inhibitory potential for 15-LOX with an IC50 of 0.12 ± 0.002 to 0.69 ± 0.5 µM and showed moderate inhibition potency for bCA II with compound 5h (IC50 = 1.26 ± 0.24 µM) being the most active. The most potent compound 5a that emerged as a dual inhibitor of both enzymes, exhibiting 24 times greater selectivity for 15-LOX over bCA II. Compound 5a exhibited dual potent inhibitory activity against both 15-LOX and bCA II enzymes having IC50 values of 0.12 ± 0.002 and 2.93 ± 0.22 µM, respectively. Molecular docking studies of potent as well as dual inhibitors were also carried out to provide an insight into the binding site interactions.

Cholinesterases inhibition and molecular modeling studies of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones.

Super-activation of cholinesterases (acetylcholinesterase and butyrylcholinesterase) are linked to various neurological problems most precisely Alzheimer's disease (AD), which leads to senile dementia. Therefore, cholinesterases (AChE & BChE) inhibition are considered as a promising strategy for the treatment of Alzheimer's disease. FDA approved drugs for the treatment of AD, belong to a group of cholinesterase inhibitors. However, none of them is able to combat or completely abrogate the disease progression. Herein, we report a series of newly synthesized chalcone derivatives with anti-AD potential. For this purpose, a series of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones were tested for their cholinesterases (AChE & BChE) inhibitory activity. All compounds were found as selective inhibitor of AChE. In piperidyl chalcones derivatives compound 1e having IC50 of 0.16 ± 0.008 µM and 2m in 2-pyrazoline chalcones with IC50 of 0.13 ± 0.006 µM, were found to be the most potent inhibitors of AChE, exhibiting ≈142 and ≈ 173-fold greater inhibitory potential compared to the reference inhibitor i.e., Neostigmine (IC50 ± SEM = 22.2 ± 3.2 µM). Molecular docking studies of most potent inhibitors were carried out to investigate the binding interactions inside the active site. Molecular docking study revealed that potent compounds and co-crystalized ligand had same binding orientation within the active site of target enzyme. Most of these compounds are selective inhibitors of AChE with a potential use against progressive neurodegenerative disorder and age related problems.

New one-pot synthesis of N-fused isoquinoline derivatives by palladium-catalyzed C-H arylation: potent inhibitors of nucleotide pyrophosphatase-1 and -3.

Various N-fused isoquinoline derivatives were synthesized using a new one-pot reaction of 1-bromo-2-(2,2-difluorovinyl)benzenes with N-H group containing heterocycles followed by intramolecular palladium-catalyzed C-H arylation. The method described gives convenient access to diverse structures of N-fused polycyclic isoquinolines. Sixteen of the synthesized compounds were screened as potential human nucleotide pyrophosphatase/phosphodiesterase 1 and 3 (h-NPP-1 and h-NPP-3) inhibitors. The most effective h-NPP-1 inhibitor showed an IC50 value as high as 0.36 ± 0.06 µM, whereas the most potent h-NPP-3 inhibitor posessed an inhibitory value of 0.48 ± 0.01 µM. Kinetic and molecular docking studies of both most effective inhibitors were carried out.

The enhanced reliability of higher national institute of health stroke scale thresholds over the conventional 6-point scale.

INTRODUCTION: It is still uncertain if higher thresholds on National Institute of Health Stroke Scale (NIHSS) are better predictors of large infarctions than the conventional 6-point cutoff. METHODS: We used 6-point and higher NIHSS thresholds including 8, 9, and 10-point to predict relative infarct areas, expressed as percentage of the affected hemisphere on axial brain computed tomography images, beginning at 5% with 5% increments each time until reaching the 40% cutoff for large infarctions, or achieving 100% sensitivity. Results were compared using area under the receiver operating characteristic curves (AUROC). RESULTS: We enrolled 151 patients of acute ischemic stroke (Mean age: 62.88 years ± 12.71; Female: 48.34%). 77 patients (50.99%) exhibited left hemisphere strokes, while 74 (49%) had right hemisphere involvement. Sensitivity values of the 6-point for infarcts measuring 5%, 10%, 20%, 30%, and 40% were 62%, 64%, 77%, 82%, and 100%, respectively. At 40% infarct-size, 8-point achieved comparable results (52%, 55%, 69%, 76%, 100%), closely aligning with the 9-point (50%, 53%, 69%, 76%, 100%). The10-point was slightly trailing behind in sensitivity at 40% infarct-core (96%). Moreover, higher thresholds exhibited improved false-positive rates (FPR). At 40% infarct size, the FPRs of 6, 8, 9, and 10 points were 39%, 27%, 27%, and 21% respectively. Higher thresholds had augmented AUROC values (0.86, 0.86, 0.89) as compared to the 6-point (0.80). Logistic regression identified 14-point as definitive cutoff for large infarctions. CONCLUSION: Higher thresholds can better differentiate small and medium infarcts as true-negatives and substantially reduce false-positive referrals for mechanical thrombectomy.

Auscultation-Based Pulmonary Disease Detection through Parallel Transformation and Deep Learning.

Respiratory diseases are among the leading causes of death, with many individuals in a population frequently affected by various types of pulmonary disorders. Early diagnosis and patient monitoring (traditionally involving lung auscultation) are essential for the effective management of respiratory diseases. However, the interpretation of lung sounds is a subjective and labor-intensive process that demands considerable medical expertise, and there is a good chance of misclassification. To address this problem, we propose a hybrid deep learning technique that incorporates signal processing techniques. Parallel transformation is applied to adventitious respiratory sounds, transforming lung sound signals into two distinct time-frequency scalograms: the continuous wavelet transform and the mel spectrogram. Furthermore, parallel convolutional autoencoders are employed to extract features from scalograms, and the resulting latent space features are fused into a hybrid feature pool. Finally, leveraging a long short-term memory model, a feature from the latent space is used as input for classifying various types of respiratory diseases. Our work is evaluated using the ICBHI-2017 lung sound dataset. The experimental findings indicate that our proposed method achieves promising predictive performance, with average values for accuracy, sensitivity, specificity, and F1-score of 94.16%, 89.56%, 99.10%, and 89.56%, respectively, for eight-class respiratory diseases; 79.61%, 78.55%, 92.49%, and 78.67%, respectively, for four-class diseases; and 85.61%, 83.44%, 83.44%, and 84.21%, respectively, for binary-class (normal vs. abnormal) lung sounds.

A comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug development.

Peptidoglycan is a carbohydrate with a cross-linked structure that protects the cytoplasmic membrane of bacterial cells from damage. The mechanism of peptidoglycan biosynthesis involves the main synthesizing enzyme glycosyltransferase MurG, which is known as a potential target for antibiotic therapy. Many MurG inhibitors have been recognized as MurG targets, but high toxicity and drug-resistant Escherichia coli strains remain the most important problems for further development. In addition, the discovery of selective MurG inhibitors has been limited to the synthesis of peptidoglycan-mimicking compounds. The present study employed drug discovery, such as virtual screening using molecular docking, drug likeness ADMET proprieties predictions, and molecular dynamics (MD) simulation, to identify potential natural products (NPs) for Escherichia coli. We conducted a screening of 30,926 NPs from the NPASS database. Subsequently, 20 of these compounds successfully passed the potency, pharmacokinetic, ADMET screening assays, and their validation was further confirmed through molecular docking. The best three hits and the standard were chosen for further MD simulations up to 400 ns and energy calculations to investigate the stability of the NPs-MurG complexes. The analyses of MD simulations and total binding energies suggested the higher stability of NPC272174. The potential compounds can be further explored in vivo and in vitro for promising novel antibacterial drug discovery.