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The enzyme α-glucosidase in the small intestine regulates blood glucose levels and stimulates the hydrolysis of oligosaccharides and polysaccharides, increasing glucose levels in the body. Inhibiting this enzyme slows glucose digestion and absorption and as a result post-prandial blood glucose levels remain low, causing decreased insulin demand. Here, we investigated the ayurvedic antidiabetic plants and virtually screened an in-house library of 478 phytochemicals of these plants against the human α-glucosidase. We identified 11 secondary metabolites, including palmitic acid α-monoglyceride, (+)-(2 R)-6-propionyloxyethyl-4′,5,7-trihydroxyisoflavanone, Abruquinone E, and Aurantiamide Acetate, among others, showed stronger interactions with the receptor than the native ligand N-acetyl cysteine. Surprisingly, except one, all of these metabolites were from Abrus precatorius L. [Fabaceae] affirming its ethnopharmacological use against diabetes. The stability of the interactions between the ligands and receptor protein was evaluated through Molecular Dynamic (MD) simulation trajectories including root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), H bonds, β-factor analysis, and binding energy calculation through MM/GBSA method. The efficacy of top metabolites in inhibiting α-glucosidase is depicted in pharmacophore analysis. A comprehensive pharmacokinetics analysis confirmed the druggability, safety, and efficiency of top drug candidates. Additionally, we predicted the interactions of these top metabolites within the biological system. The medicinal properties described in this study will help develop active drug candidates for therapeutic purposes. Further experiments are recommended to prove the effectiveness of these metabolites in inhibiting the α-glucosidase enzyme for exploring their potential in the treatment of diabetes.

The primary goal of current study is to formulate a novel mathematical model employing the Prabhakar fractional operator, aimed at examining the dynamic behaviour of Jeffrey fluid flow and heat transfer phenomena under ramped wall temperature conditions. Our investigation entails a meticulous investigation of magnetohydrodynamic (MHD) natural convective flow within Jeffrey fluids, where we derive precise analytical solutions utilizing the Prabhakar fractional derivative, characterized by a non-singular type kernel. Furthermore, our study integrates fundamental principles such as Fick’s and Fourier’s laws into the model, leveraging a multi-parameter Mittag-Leffler kernel associated with the fractional operator. We delve into the intricacies of fluid flow near an infinitely vertical plate, considering characteristics such as velocity u0. To address the complexities of the problem, we express it in context the of partial differential equations along side generalized boundary conditions, employing a set of appropriate variables to transform these equations into a dimensionless form. Utilizing Laplace transform, we analyse the equations of fractional system, presenting outcomes both in the form of series and through specialized functions. We systematically explore the influence of key parameters α, Pr, β, Gm, Sc, γ, Gr on fluid flow dynamics, unveiling significant insights. Our comparative analysis reveals the superior performance of the Prabhakar-like non-integer approach over existing operators, substantiated by graphical representations of the results. Additionally, we extend our investigation to various limiting cases, including Newtonian fluids and second-grade, in both fractionalized and classical forms, thus highlighting the versatility and applicability of our proposed model within fluid dynamics research.

Scientists have been concentrating on storing and converting energy resources in significant scenarios as the entire globe is currently experiencing an extreme energy shortage issue owing to a variety of factors. Supercapacitors and other energy storage technologies based on transition metals are currently in high demand. In this study, multi-component NiO/g-C3N4/CNTs and NiO/g-C3N4/CNTs/TiO2 nanocomposites were effectively constructed, characterised, and the performance of the synthesized materials was reported as super capacitance. The synthesis of NiO/g-C3N4/CNTs and NiO/g-C3N4/CNTs/TiO2 using thermal, heat-treatment, hydrothermal and ultrasonic exfoliation techniques. With impressive findings, the characterisation of X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS) was conducted. Cyclic Voltammetry (CV), Galvanic Charge Discharge (GCD), and scan rate influence on specific capacitance were used in the electrochemical experiments. Results of Electron Impedance Spectroscopy (EIS) experiments revealed that the NiO/g-C3N4/CNTs/TiO2 electrode had a higher specific capacitance (388.76 Fg−1) than the NiO/g-C3N4/CNTs electrode (362.12 Fg−1). In comparison to NiO/g-C3N4/CNTs (360 Fg−1), the NiO/g-C3N4/CNTs/TiO2 electrode had a gravimetric capacitance of 541 Fg−1. The GCD curve and EIS results also support the conclusion that the NiO/g-C3N4/CNTs/TiO2 electrode material is an excellent candidate with impressive capacitive performance to be used as an energy storing source or supercapacitor because TiO2 contents are available, improving the charge transfer capability linked with CNTs bridged in g-C3N4 interlayered stacked and porous structure, ensuring ion diffusion pathways for better and improved conductivity.

Metal-organic frameworks have been used as antibacterial agents because of their effective antibacterial properties. In this research, nanocomposites of copper (II)- benzene-1,4-dicarboxylic acid metal–organic framework with iron oxide [Cu-MOF@Fe3O4] were prepared via a simple hydrothermal route. X-ray analysis reveals the crystallinity of the structure while FTIR analysis confirms the existence of Cu-based MOFs functional group. Cu-MOF@Fe3O4 scans using Scanning Electron Microscopy (SEM) reveal irregular clusters of cubic particles fused with Fe3O4 nanoparticles. Energy Dispersive X-ray (EDX) spectrum of Cu-MOF@Fe3O4 provides the evidence of elemental composition by showing the peaks of iron, oxygen, copper and carbon. Using the minimum inhibitory concentration (MIC) and zone of inhibition assays, the antimicrobial activity of the Cu-MOF and Cu-MOF@Fe3O4 against E. coli and B. subtilis were evaluated. The antibacterial results have shown that the Cu-MOF@Fe3O4 has higher antibacterial performance against E. coli as compared with B. subtilis as compared to Cu-MOF, Fe3O4 and ligands only. On the other hand, the Cu-MOF@Fe3O4 composites exhibit excellent antifungal potential when compared to the ligand, commercial nanoparticles, Cu(NO3)2·3H2O, iron oxide, Cu-MOF. The exploration of antibacterial mechanism revealed that the Cu-MOF@Fe3O4 composite favors slow release of metal ions and prolonged biocidal effect.

Background: Leishmaniasis is the second and fourth highest cause of mortality and morbidity respectively among all tropical diseases. Recurrence in the onset of leishmaniasis is a major problem that needs to be addressed to reduce the case fatality rate and ensure timely clinical intervention. Here we are investigating the association of risk factors with recurrent cutaneous leishmaniasis to address this issue. Material and methods: Patients received by Nasser Ullah Khan Babar Hospital in Peshawar, Pakistan from March 2019 to July 2020 were enrolled in this study. Those patients who developed symptoms after completion of treatment were included in Group-A while those who had atypical scars like leishmaniasis but were negative for cutaneous leishmaniasis were included in the comparison group tagged as Group B. All those individuals who had completed six weeks of treatment for CL but had normal complete blood counts (CBC) were included to avoid other underlying immunological pathologies, while we excluded those participants who had co-morbidities like diabetes, liver disease, cardiac disease, and pregnant and lactating women through their history Association was tested between Group-A and Group-B with other explanatory variables through chi-square test. The regression model was proposed to determine the predictors. Result: A total of 48 participants of both sexes were included in the study with a mean age of 32.2 ± 15.10. The data suggest that females are overrepresented among the patients with recurrent leishmaniasis [21(53.8 %,); p = 0.07]. Compared to patients; healthy participants had a higher proportion of adults (19–59 years) versus adolescents (13–18 years) [26(66.7 %) vs 07(17.9), p = 0.004]. Multivariate logistic regression analysis shows that females are 2.1 times more prone to infections among cases as compared to healthy individuals [unadjusted OR 2.20, 95 % confidence interval (CI) 1.5–10.6, p = 0.02; adjusted OR 2.1, 95 % CI 1.50–10.69, p = 0.02]. We propose that patients receiving intradermal were less likely to be infected as compared to those receiving intralesional injections [unadjusted OR 0.07.0, 95 % confidence interval (CI) 1.18–3.37, p = 0.03; adjusted OR 0.06, 95 % CI 1.18–3.38, p = 0.03]. Conclusion: Old age (adults) and sex (females) were the strongest predictors to be associated with recurrent leishmaniasis. Similarly, the choice of intradermal as compared to intralesional injection and the prolonged treatment duration were strongly associated with greater chances of recurrence.

The purpose of this study is to shed light on the extent of intellectual capital efficiency (ICE) and the relationship of its three components (human capital efficiency, structural capital efficiency, and relational capital efficiency) with Islamic banking performance (in terms of return on assets, return on equity, and Tobin's q) in Muslim countries. We develop hypotheses on this relationship drawing on the resource-based theory. The study employs a two-step system generalized method of moments (2SYS-GMM) estimator to analyze the data collected from 129 Islamic banks in 29 Muslim countries over the period from 2008 to 2017. The study provides evidence that the performance of Islamic banks (IBs) is driven primarily by investment in ICE. The results indicate that structural capital efficiency (SCE) and relational capital efficiency (RCE) are the essential drivers of value in achieving high performance at Islamic banks. The results reveal that human capital efficiency (HCE) negatively affects the performance of IBs. Bank size and foreign ownership are also identified as significant drivers of IBs performance. This study helps IBs to maintain their ICE assets because they are the main drivers for sustaining competitive advantage as well as raising bank productivity. Our findings can help stakeholders and policymakers to recognize the significant components of ICE and a reasonable allocation among them for improving bank performance. To the best of our knowledge, this is the first empirical study to evaluate ICE and its relationship with Islamic banking performance in 29 Muslim countries across the Middle East, South Asia, and Southeast Asia.

A new approach to investigates the analytical solutions of the mathematical fractional Casson fluid model that is described by the Yang-Abdel-Cattani fractional operator having Rabotnov exponential kernel near an infinitely vertical plate. The phenomenon has been expressed in terms of partial differential equations, then transformed the governing equations in non-dimentional form. For the sake of better rheology of Casson fluid, developed a fractional model by applying the new definition of Yang-Abdel-Cattani fractional derivative operator having Rabotnov exponential kernel that describe the generalized memory effects. For seeking exact solutions in terms of Mittag-Leffler functions, for fluid velocity, concentration and temperature, Laplace integral transformation method is used to solve the fractional model. For several physical significance of various fluid parameters such as α, β, Pr, Gr, Gm, Sc on velocity, concentration and temperature distributions are demonstrated through various graphs and it is noticed that the Yang-Abdel-Cattani fractional parameter portrayed the retardation effect on momentum and energy profile, but it is visualized that for small values of Casson fluid parameter the velocity profile is higher. Furthermore, for being validated the acquired solutions, some limiting models such as ordinary Newtonian model had recovered from Yang-Abdel-Cattani fractional Casson fluid. Moreover, the graphical representations of the analytical solutions illustrated the main results of the present work. Also, in the literature, it is observed that to derived analytical results from fractional fluid models developed by the various fractional operators, is difficult and this article contributing to answer the open problem of obtaining analytical solutions the fractionalized fluid models.

In this article, a new approach to study the fractionalized Maxwell fluid is described by the Prabhakar fractional derivative near an exponentially accelerated vertical plate together with exponentially variable velocity, energy and mass diffusion through a porous media is critically examined. The phenomena has been described in forms of partial differential equations along with heat and mass transportation effect taken into account. The Prabhakar fractional operator which was recently introduced is used in this work together with generalized Fick's and Fourier's law. The fractionalized model is transfromed into non-dimensional form by using some suitable dimensionless quantities. The non-dimensional developed fractional model for momentum, thermal and diffusion equations based on Prabhakar fractional operator has been solved analytically via Laplace transformation method and calculated solutions expressed in terms of Mittag-Leffler special functions. Graphical demonstration are made to characterized the physical behavior of different parameters and significance of such system parameters over the momentum, concentration and energy profiles. Moreover, for results validation, comparative study among limiting models derived from fractionalized Prabhakar Maxwell fluid such as fractional and classical fluid models for Maxwell and Newtonian are performed. Further, it is observed from the graphs the valocity curves for classical fluid models relatively higher as compared to fractional fluid models, and fractional approach is more realistic and convenient as compared to classical approach.

In this article, heat source impact on unsteady magnetohydrodynamic (MHD) flows of Prabhakar-like non integer second grade fluid near an exponentially accelerated vertical plate with exponentially variable velocity, temperature and mass diffusion through a porous medium. For the sake of generalized memory effects, a new mathematical fractional model is formulated based on newly introduced Prabhakar fractional operator with generalized Fourier's law and Fick's law. This fractional model has been solved analytically and exact solutions for dimensionless velocity, concentration and energy equations are calculated in terms of Mittag-Leffler functions by employing the Laplace transformation method. Physical impacts of different parameters such as α, Pr, β, Sc, Gr, γ, Gm are studied and demonstrated graphically by Mathcad software. Furthermore, to validate our current results, some limiting models such as classical second grade model, classical Newtonian model and fractional Newtonian model are recovered from Prabhakar fractional second grade fluid. Moreover, compare the results between second grade and Newtonian fluids for both fractional and classical which shows that the movement of the viscous fluid is faster than second grade fluid. Additionally, it is visualized that for both classical second grade and viscous fluid have relatively higher velocity as compared to fractional second grade and viscous fluid.

Nanocomposites consisting of polyvinyl alcohol embedded with nanoparticles of Zn0.80Co0.1Ni0.1Fe2O4 and ZnFe2O4 were successfully synthesized by employing a facile two-steps process. The nanoparticles of Zn0.80Co0.1Ni0.1Fe2O4 and ZnFe2O4 were synthesized via a micro emulsion procedure and then embedded into a polyvinyl alcohol matrix by an ultrasound-assisted in-situ emulsion. The result showed that the prepared nanoparticles of Zn0.80Co0.1Ni0.1Fe2O4 & ZnFe2O4 diffuse homogeneously in a polyvinyl alcohol matrix, maintaining the particle shape and size of the Zn0.80Co0.1Ni0.1Fe2O4 nanoparticles. Transmission electron microscope images revealed that polyvinyl alcohol chains have encircled the Zn0.80Co0.1Ni0.1Fe2O4 & ZnFe2O4 nanoparticles. The interaction between the polyvinyl alcohol and the nanoparticles in the prepared nanocomposites was confirmed by Fourier-transform infrared spectroscopy via the shifting of bands revealed from the Fourier-transform infrared spectra. Dielectric studies explained the decreasing trend by varying concentrations of nanoparticles with a constant polymer concentration. The dielectric constant and dielectric loss both revealed a decreasing trend by varying the concentration of the nanoparticles with a constant polymer concentration. This occurred due to the grain boundary effect which becomes dominant at low frequencies. The Transmission electron microscope images result shows that polycrystalline Zn0.80Co0.1Ni0.1Fe2O4 & ZnFe2O4 nanoparticles with an average size of 10–15 nm were incorporated with PVA to form nanocomposites. Keywords: Nanocomposites, Polyvinyl alcohol (PVA), Ultrasound-assisted, In-situ emulsions

Summary: Cell membrane is the first medium from where a cell senses and responds to external stress stimuli. Exploring the tension changes in cell membrane will help us to understand intracellular force transmission. Here, a biosensor (named MSS) based on fluorescence resonance energy transfer is developed to visualize cell membrane tension. Validity of the biosensor is first verified for the detection of cell membrane tension. Results show a shear stress-induced heterogeneous distribution of membrane tension with the biosensor, which is strengthened by the disruption of microfilaments or enhancement of membrane fluidity, but weakened by the reduction of membrane fluidity or disruption of microtubules. These findings suggest that the MSS biosensor is a beneficial tool to visualize the changes and distribution of cell membrane tension. Besides, cell membrane tension does not display obvious polar distribution, indicating that cellular polarity changes do not first occur on the cell membrane during mechanical transmission. : Sensor; Molecular Biology; Membrane Architecture; Biophysics Subject Areas: Sensor, Molecular Biology, Membrane Architecture, Biophysics

Conservation tillage may improve yield of cotton in addition to improvement in soil quality if practiced for longer period. However, the practice may not be productive in short-term particularly when severe weeds are infesting the crops such as Cynodon dactylon, Conyza canadensis, Tribulus terrestris, and Cyperus rotundus, etc. Recent studies indicate that conventional tillage (CT) is more productive than zero tillage (ZT)/reduced tillage (RT). Performance of cotton under three tillage systems, viz., ZT, RT and CT; and five herbicides, i.e., haloxyfop-R-methyl 10.8 EC (108 g a.i. ha−1), lactofen 24 EC (168 g a.i. ha−1), haloxyfop 10.8 EC + lactofen 24 EC, hand weeding, and weedy check were evaluated during 2010-2011 at Gomal University, D.I. Khan, Pakistan, to explore the best management option for effective weed control, enhanced yield and quality of cotton grown after wheat. The results revealed that hand weeding and Haloxyfop as post emergence alone or in combination with Lactofen reduced weed density to the minimum irrespective of the tillage systems. Excessive rainfall and cooler temperature limited cotton growth and yield in 2010. The adverse weather conditions had more adverse effect on boll weight under ZT and RT than CT. Haloxyfop + lactofen produced higher seed cotton yield in RT than ZT, however, it could not exceed CT. Broad-spectrum herbicides × CT produced the highest number of bolls/plant, boll weight and seed cotton yield. Fiber quality and net returns were also the highest in broad-spectrum herbicides × CT. In conclusion, broad-spectrum herbicides under CT were more productive in wheat based cropping system on silty clay soil of D.I. Khan.

This paper focuses on obtaining exact solutions for the nonlinear Van der Waals gas system using the modified Khater method. Renowned as one of the latest and most precise analytical schemes for nonlinear evolution equations, this method has proven its efficacy by generating diverse solutions for the model under consideration. The governing equation is transformed into an ordinary differential equation through a well-suited wave transformation. This analytical simplification makes it possible to use the provided methods to derive trigonometric, rational, and hyperbolic solutions. To illuminate the physical behavior of the model, graphical plots of selected solutions are presented. By selecting appropriate values for arbitrary factors, this visual representation enhances comprehension of the dynamical system. Furthermore, the system undergoes a certain transformation to become a planar dynamical system, and the bifurcation analysis is examined. Additionally, the sensitivity analysis of the dynamical system is conducted using the Runge–Kutta method to confirm that slight alterations in the initial conditions have minimal impact on the stability of the solution. The presence of chaotic dynamics in the Van der Waals gas system is explored by introducing a perturbed term in the dynamical system. Two and three-dimensional phase profiles are used to illustrate these chaotic behaviors.

In our continuous efforts to find out leads against the enzyme 15-lipoxygenase (15-LOX), the current study deals with the synthesis of a series of new N-alkyl/aralkyl/aryl derivatives of 2-(4-ethyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)methylacetamide (7a-n) with anti-LOX activities. The synthesis was started by reacting phenylisocyanate with isonipecotate that sequentially converted into N-substituted ester (1), hydrazide (2), semicarbazide (3) and N-ethylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4). The final compounds, 7a-n, were obtained by reacting 4 with various N-alkyl/aralkyl/aryl electrophiles. Both the intermediates and target compounds were characterized by FTIR, 1H, 13C NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and screened against soybean 15-LOX by chemiluminescence method. The eight compounds 7e, 7j, 7h, 7a, 7g, 7b, 7n, 7c showed potent inhibitory activities against 15-LOX with values ranging from IC50 0.36 ± 0.15 μM (7e) to IC50 6.75 ± 0.17 μM (7c) compared with the reference quercetin (IC50 4.86 ± 0.14 μM) and baicalein (IC50 2.24 ± 0.13 μM). Two analogues (7l, 7f) had significantly outstanding inhibitory potential with IC50 values 12.15 ± 0.23 μM and 15.54 ± 0.26 μM, whereas, the derivatives 7i, and 7d displayed IC50 values of 21.56 ± 0.27 μM, 23.59 ± 0.24 μM and the compounds 7k, 7m were found inactive. All analogues exhibited blood mononuclear cells (MNCs) viability >75 % at 0.25 mM concentration as determined by MTT method. Calculated pharmacokinetic properties projected good lipophilicity, bioavailability and drug-likeness properties and did not violate Lipinski's/Veber rule. Molecular docking studies revealed lower binding free energies of all the derivatives than the reference compounds. The binding free energies were −9.8 kcal/mol, −9.70 k/mol and −9.20 kcal/mol for 7j, 7h and 7e, respectively, compared with the standard quercetin (−8.47 kcal/mol) and baicalein (−8.98 kcal/mol). The docked ligands formed hydrogen bonds with the amino acid residues Gln598 (7e), Arg260, Val 126 (7h), Gln762, Gln574, Thr443, Arg580 (7j) while other hydrophobic interactions observed therein further stabilized the complexes. The results of density functional theory (DFT) revealed that analogues with more stabilized lower unoccupied molecular orbital (LUMO) had significant enzyme inhibitory activity. The data collectively supports these molecules as leads against 15-LOX and demand further investigations as anti-inflammatory agents.

This study focuses on finding effective solutions to a mathematical equation known as the Lonngren wave equation. The solutions from the Lonngren wave equation can be used to evaluate electromagnetic signals in cable lines and sound waves in stochastic systems. The main equation is transformed into an ordinary differential equation by utilizing a suitable wave transformation, allowing for the exploration of mathematical models by using the modified Khater technique to detect the exact solution of a solitary wave. We use the provided method to derive the trigonometric, rational, and hyperbolic solutions. To illustrate the model’s physical behavior, we also present graphical plots of selected solutions to illustrate the physical behavior of the model. By choosing appropriate values for arbitrary factors, the visual representation enhances the understanding of the dynamical system. Furthermore, the system is transformed into a planar dynamical system, and phase portrait analysis is conducted. Additionally, the sensitivity analysis of the dynamical system confirms that slight changes in the initial conditions will have minimal impact on the stability of the solution. The existence of chaotic dynamics in the Lonngren wave equation is explored by introducing a perturbed term in the dynamical system. Two and three-dimensional phase portraits will be used to demonstrate these chaotic behaviors.

Rubella is an infectious disease that can spread globally. It spreads in the subtropics as well as the tropics. Although it is commonly thought to be a non-fatal condition, there are several circumstances in which it can be fatal. Pregnant women infected with the Rubella virus face a high risk of fetal development. The main goal of this study is to look into a model for the spread of Rubella while considering a vaccination campaign as a control measure. The positivity and boundedness of the re-infection rubella transmission and vaccination model are investigated. The local and global stability of the equilibrium points is examined. The sensitivity of parameters is also investigated. Three different techniques forward Euler, RK-4, and non-standard finite difference (NSFD) method are developed for the numerical solution, and their simulation results are examined. Among these three, the NSFD method is superior due to its convergence and positive behavior for all step size values. For some values of the step size, the other two techniques failed to produce positivity and convergent solutions. Analytically, the proposed model's convergence, positivity, boundedness, and consistency are investigated. Finally, the impact of the Rubella vaccine on infected populations has been examined, revealing that vaccination is one of the most effective ways to prevent rubella transmission.

This work attempts to study the numerical solution of nonlinear delayed Immunized Susceptible Latent Infected and Recovered (MSLIR) epidemic model of HBV disease. Reproduction number, equilibria and stability are discussed. Three different numerical techniques, Euler, RK-4 and the non-standard finite difference (NSFD) techniques are used for the numerical solution of the model. The proposed technique is independent of the size of the time step, while forward Euler and RK-4 depend on the size of a time step and retains all essential characteristics of the continuous MSLIR epidemic model like positivity and stability of equilibrium, while well-known forward Euler and RK-4 cannot sustain these characteristics. Therefore, the proposed (NSFD) technique becomes a more efficient and reliable numerical technique than the forward Euler and RK-4 scheme. Numerical simulations are presented for the validation of the obtained results.

A series of novel triazole analogs (10a-k) bearing piperidine were synthesized in an aprotic solvent on the most effective pharmacophore with acetylcholinesterase (AChE) and α-glucosidase inhibitory activity. Triazole analogs (10a-k) were obtained in excellent yields (75–90 %) and characterized by EI-MS, IR, 13C NMR and 1H NMR. The newly synthesized triazole analogs (10a-k) showed potent AChE inhibitory activity in the range of Ki = 0.0155 ± 1.25 µM to 0.557 ± 0.50 µM, IC50 = 0.031 ± 0.85 to 0.537 ± 0.76 µM than Eserine (0.04 ± 0.001 µM) having strong electron-withdrawing fluorine group on the pyridine ring was recorded as a most potent inhibitor of AChE while (%) inhibition against α-glucosidase was ranging between 52.36 ± 1.67 to 85.35 ± 1.39. The kinetic study predicted that triazole analogs (10a-k) followed the un-competitive and mixed type of inhibition against AChE. In silico molecular docking was performed at the active site of the AChE co-crystal structure (PDB ID:1NEN). The results of molecular docking corelate will with the experimental findings.

As a DNA mismatch repair deficit (dMMR) anticancer medication, and a humanized monoclonal antibody (hmAb), Tislelizumab has attracted significant interest in recent years. The programmed cell death protein-1 (PD-1) and its ligands (PD-L1/CD274/B7-H1 and PDL2/CD273) may bind to each other with great affinity. This binding prevents activated T-cells from continuing to proliferate, produce cytokines, and engage in cytotoxic action. The B7:PD-1 inhibitory immunological checkpoint receptor binds to the B7-2(CD86) B-lymphocyte activation antigen. This paper presents Tislelizumab's molecular docking and dynamics simulations with the receptor B7-2(CD86) and its downstream signaling proteins CTLA-4 and IL-6. When docked to B cell stimulatory factor-2 soluble IL-6 receptor alpha (sIL6Ra/CD126), Tislelizumab had a strong binding affinity of 329 kcal/mol and provided an excellent quality model with an LGscore of 4.54. The type I membrane protein B7-2(CD86), a member of the immunoglobulin superfamily, responded to docking with an affinity of −332.35 kcal/mol and LGscore of 2.54. Docking to the immune checkpoint protein receptor cytotoxic T-lymphocyte-associated protein-4 (CTLA-4/CD152) had a binding affinity of −305.91 kcal/mol, facilitating immunological control and cellular dissociation. Tislelizumab and these target proteins exhibited persistent and advantageous interactions in molecular dynamics studies. The STRING functional protein-protein network analysis supported our in silico docking and dynamic simulation results. This analysis also included comparisons of the binding modes of mAbs to protein receptors involved in the cancer hallmark mechanism(s), demonstrating that IL-6, B7-2, and CTLA-4 act and are inhibited in group-mode. Functional enrichment analysis and molecular modelling supported the relationship between the hallmarks of the tumor microenvironment that link inflammation to immunity. Tislelizumab may therefore be able to prevent these three proteins from acting. These findings may also shine light on Dostarlimab's mode of action, which in 2022 achieved ground-breaking success in a clinical study for colorectal cancer.

Stripe rust is a continuous threat to wheat crop all over the world. It causes considerable yield losses in wheat crop every year. Continuous deployment of adult plant resistance (APR) genes in newly developing wheat cultivars is the most judicious strategy to combat this disease. Herein, we dissected the genetics underpinning stripe rust resistance in Pakistani wheat germplasm. An association panel of 94 spring wheat genotypes was phenotyped for two years to score the infestation of stripe rust on each accession and was scanned with 203 polymorphic SSRs. Based on D´ measure, linkage disequilibrium (LD) exhibited between loci distant up to 45 cM. Marker-trait associations (MTAs) were determined using mixed linear model (MLM). Total 31 quantitative trait loci (QTLs) were observed on all 21 wheat chromosomes. Twelve QTLs were newly discovered as well as 19 QTLs and 35 previously reported Yr genes were validated in Pakistani wheat germplasm. The major QTLs were QYr.uaf.2AL and QYr.uaf.3BS (PVE, 11.9%). Dissection of genes from the newly observed QTLs can provide new APR genes to improve genetic resources for APR resistance in wheat crop.

Ru(bpy)32+/TPA system is a tremendously important electrochemiluminescence (ECL) system. Its ECL properties depend significantly on the electrodes used. Although it is well studied at the gold electrode, the ECL of Ru(bpy)32+/TPA system is considerably less studied at other electrodes. In this study, the comparative ECL studies of Ru(bpy)32+/TPA system on glassy carbon, platinum, and palladium electrodes were carried out. Particularly, the ECL of Ru(bpy)32+/TPA system at Pd electrode has been studied for the first time. Our results elucidated that platinum and palladium electrodes could generate strong ECL in slightly alkaline while glassy carbon in neutral pH conditions. An increase in the intensity of the ECL signal was observed in surfactant media. The study promotes a better understanding of Ru(bpy)32+/TPA ECL systems.

In this article, a dynamical model with advection-diffusion, elucidating the transmission process of disease infection type computer virus, is studied. Such kind of systems help to alleviate the effects of virus by prior predictions described in the model. The existence and uniqueness of the solutions of the system is investigated. A solution space (Banach space) is considered to make the possibility of existence of the solutions of proposed system. A closed and convex subset is defined in the Banach space, in which the solutions of the coupled system are optimized. The essential explicit estimates for the solutions are also calculated for the corresponding auxiliary data. Moreover, a non-standard finite difference scheme is applied to find the approximate solution of the prescribed problem. For the validity of the proposed scheme, the possession of some important structural properties by the applied numerical technique are presented. These structural properties are consistency and stability. To prove the numerical stability, Von-Neumann criteria is adopted. In the study of such population dynamics type models, positivity is one of the most important physical properties of the numerical scheme that must be preserved. To prove the positivity of the numerical method, a reliable result is established. The validation of the present study is shown by illustrating an example. The behaviors of the state variables are described by plotting the graphs of the associated example.

The classical calculus due to the fact that it assumed as the instant rate of change of the output, when the input level changes. Therefore it is not able to include the previous state of the system called memory effect. But in the Fractional Calculus (FC), the rate of change is affected by all points of the considered interval, so it is able to incorporate the previous history/memory effects of any system. Due to the importance of this effect we used the modern concept of the Caputo-Fabrizio fractional derivative on the considered Jeffrey fluid model. In this paper the effect of Newtonian heating, concentration and velocity on unsteady MHD free convective flow of Jeffrey fluid over long vertical an infinite ramped wall nested in porous material are discussed. Exact analytical solutions are derived via Laplace transformation technique for principal equations of energy, concentration and ramped velocity. The prime features of various coherent parameters are deliberated and illuminated with the aid of plotted graphs. A comparative study to show the significance of fractional order model with an integer order model is accomplished. The fractional order model is found to be the best choice for explaining the memory effect of the considered problem. It is identified that temperature distribution, concentration and ramped velocity profiles for fractional model are converges to an ordinary model when fractional parameter tends to integer order, which shows that fractional model is more appropriate to explicate experimental results.

In the study presented here, a novel chlorobenzylated bi-heterocyclic hybrid molecule (7) was synthesized and its structural confirmation was carried out by IR, 1H-NMR, 13C-NMR and CHN analysis data. This compound 7 was subjected to biological study with B16F10 mouse melanoma cells. The anti-proliferative results showed that 7 showed no significant toxicity at concentrations ranging of 0–44 μM. The treatment of B16F10 cells with 7 at aforementioned concentration range indicated that migration of cells was significantly lower than that of the control cells in a dose dependent manner. The possible migration inhibitory effect of these melanoma cells was further evaluated through gelatinolytic activity of MMP-2 and MMP-9 secreted from B16F10 cells. It was inferred from our results that 7 was not affecting the expression and activity of these enzymes. Some other zinc-dependent matrix metalloproteinases (MMPs) were involved in the inhibitory progression. Taken together, compound 7 inhibited migrations of B16F10 mouse melanoma cells. Therefore, it may deserve consideration as a potential agent for the treatment of cancer. Keywords: 2-Aminothiazole, Triazole, Anti-proliferation, Matrix metalloproteinase, Zymography

HIV/AIDS is a distressing and incurable disease of the human beings. In this article, we have proposed a numerical structure for the HIV/AIDS compartmental model with diffusion and delay process. The proposed scheme has the proficiency to preserve the positivity of the state variables. Also, the proposed scheme leads to the consistency and stability. Two equilibrium states of the model have been described. Moreover, the stability of the scheme is examined at these two states. The contribution of the basic reproductive number R0, in stability analysis is also investigated. The bifurcation value of the infection parameter γ, for different situations of τ is also investigated. Graphical solutions with the aid of computer simulations are presented to clarify the paramount features of the proposed numerical design.

Analysis of mathematical models projected for COVID-19 presents in many valuable outputs. We analyze a model of differential equation related to Covid-19 in this paper. We use fractal-fractional derivatives in the proposed model. We analyze the equilibria of the model. We discuss the stability analysis in details. We apply very effective method to obtain the numerical results. We demonstrate our results by the numerical simulations.

Two series of new N-aryl derivatives (9a-j; 10a-j) of 2-(4-ethyl-5-(3-chlorophenyl)-4H-1,2,4-triazol-3-ylthio)acetamide and 2-(4-phenyl-5-(3-chlorophenyl)-4H-1,2,4-triazol-3-ylthio)acetamide were synthesized by the successive conversions of 3-chlorobenzoic acid (a) into its respective ester (1) hydrazide (2), and into N-substituted 1,2,4-triazole (5, 6) via 3 and 4, respectively. The target compounds (9a-j; 10a-j) were obtained by the reaction of N-substituted 1,2,4-triazole (5, 6) with various electrophiles (8a-j), in N,N-dimethyl formamide (DMF) and sodium hydride (NaH). The synthesized analogues were characterized by using FTIR, 1H, 13C NMR spectroscopy, EIMS and HREIMS spectrometry. All the synthesized compounds, 9a-j and 10a-j, were evaluated for their inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinestrase (BChE), where these compounds showed moderate to good activities against the tested enzymes. Compounds 9j and 10f displayed potent inhibitory potential (IC50 5.41 ± 0.24 & 13.57 ± 0.31 μM, respectively) against AChE while compound 9j exhibited potent inhibitory activity (IC50 7.52 ± 0.18 μM) against BChE. Other compounds showed good to moderate inhibitory activities against the said enzymes in the range of IC50 14.29–43.94 μM for AChE and IC50 21.59–41.54 μM for BChE. To rationalize the binding site interactions, docking studies were carried out. All docked compounds were found to bind in the active site with similar binding orientation and favorable binding interactions with the surrounding amino acids.

2,5-Disubstituted 1,3,4-oxadiazole compounds are one of the most attractive classes for researchers due to their pharmacological activities. In the current research, a new series of 2-[[5-alkyl/aralkyl-1,3,4-oxadiazol-2-yl]thio]-N-[4-(4-morpholinyl)phenyl]acetamides (6a–m) were prepared by converting different aryl/aralkyl organic acids (1a–m) successively into corresponding esters (2a–m), hydrazides (3a–m) and 5-aryl/aralkyl-1,3,4-oxadiazol-2-thiols (4a–m). Finally, the target compounds 6a–m were synthesized by stirring 5-aryl/aralkyl-1,3,4-oxadiazol-2-thiols (4a–m) with 2-bromo-N-[4-(4-morpholinyl)phenyl]acetamide (5) in the presence of N,N-dimethylformamide (DMF) and sodium hydride (NaH). The structures of the synthesized compounds were elucidated through IR, 1H-NMR, 13C-NMR and mass spectral data. The compounds were also screened for antimicrobial and hemolytic activity and most of them were found to be active against the selected microbial species at variable extent relative to reference standards. The compounds, 6d and 6f were active against the selected panel of microbes and the former was the most potent one. This series showed less toxicity and may be considered for further biological screening and application trial except 6h and 6l, possessing higher cytotoxicity.

1,3,4-Oxadiazole bearing compounds are one of the most attractive class for researchers due to their biological activities. In the undertaken research, a number of N-substituted derivatives of 2-(5-(1-(phenylsulfonyl)piperidin-4-yl)-1,3,4-oxadiazol-2-ylthio)acetamide (6a–n) were synthesized through a series of steps. The reaction of benzenesulfonyl chloride with ethyl isonipecotate yielded ethyl 1-(phenylsulfonyl)piperidin-4-carboxylate (1), which was further converted into 1-(phenylsulfonyl)piperidin-4-carbohydrazide (2) and 5-(1-(phenylsulfonyl)piperidin-4-yl)-1,3,4-oxadiazol-2-thiol (3) respectively. The target compounds 6a–n were synthesized by the reaction of compound 3 with different N-aralkyl/aryl substituted 2-bromoacetamides (5a–n) in the presence of a weak base and polar aprotic solvent. The structures of the synthesized compounds were elucidated through 1H-NMR, IR and mass spectral data. The synthesized compounds were screened against Gram-negative and Gram-positive bacteria and exhibited moderate to talented activity.

Heterocyclic compounds are the most attractive class for researchers due to their biological activities. In the undertaken research, a number of N-(5-chloro-2-methoxyphenyl)-4-(5-substituted-1,3,4-oxadiazol-2-ylthio)butanamide (6a–k) compounds were prepared by converting multifarious phenyl/aryl/aralkyl/heterocyclic organic acids (1a–k) consecutively into the corresponding esters (2a–k), hydrazides (3a–k) and 5-substituted-1,3,4-oxadiazol-2-thiols (4a–k). Finally, the target compounds 6a–k were synthesized by stirring 5-substituted-1,3,4-oxadiazol-2-thiols (4a–k) with N-(5-chloro-2-methoxyphenyl)-4-bromobutanamide (5) in the presence of N,N-dimethylformamide (DMF) and sodium hydride (NaH). The structure elucidation of the synthesized compounds was processed through 1H-NMR, IR and mass spectral data. The synthesized compounds were screened against lipoxygenase enzyme (LOX) and showed moderately good activities relative to the reference standard Baicalein.

Inflammation is a multifaceted phenomenon triggered by potentially active mediators acutely released arachidonic acid metabolites partially in lipoxygenase (LOX) pathway which are primarily accountable for causing several diseases in humans. It is widely believed that an inhibitor of the LOX pathway represents a rational approach for designing more potent antiinflammatory leads with druggable super safety profiles. In our continual efforts in search for anti-LOX molecules, the present work was to design a new series of N-alkyl/aralkyl/aryl derivatives (7a-o) of 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol which was commenced in seriate formation of phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol (4). The aimed compounds were obtained by reacting 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol with assorted N-alkyl/aralkyl/aryl electrophiles. All compounds were characterized by FTIR, 1 H-, 13 C-NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and screened against soybean 15-LOX for their inhibitory potential using chemiluminescence method. All the compounds except 7m and 7h inhibited the said enzyme remarkably. Compounds 7c,7l, 7j and 7a displayed potent inhibitions ranging from IC 50 1.92 ± 0.13 µM to 7.65 ± 0.12 µM. Other analogues 7g, 7o, 7e, 7b, 7d, 7k and 7n revealed excellent inhibitory values ranging from IC 50 12.45 ± 0.38 µM to 24.81 ± 0.47 µM. All these compounds did not reveal DPPH radical scavenging activity. Compounds 7i-o maintained > 90 % human blood mononuclear cells (MNCs) viability at 0.125 mM as assayed by MTT whilst others were found toxic. Pharmacokinetic profiles predicted good oral bioavailability and drug-likeness properties of the active scaffolds. SAR investigations showed that phenyl substituted analogue on amide side decreased inhibitory activity due to inductive and mesomeric effects while the mono-alkyl substituted analogues were more active than disubstituted ones and ortho substituted analogues were more potent than meta substituted ones. MD simulation predicted the stability of the 7c ligand and receptor complex as shown by their relative RMSD (root mean square deviation) values. Molecular docking studies displayed hydrogen bonding between the compounds and the enzyme with Arg378 which was common in 7n, 7g, 7h and baicalein. In 7a and quercetin, hydrogen bonding was established through Asn375. RMSD values exhibited good inhibitory profiles in the order quercetin (0.73 Å) < 7 g < baicalein < 7a < 7n < 7 h (1.81 Å) and the binding free energies followed similar pattern. Density functional theory (DFT) data established good correlation between the active compounds and significant activity was associated with more stabilized LUMO (lowest unoccupied molecular orbitals) orbitals. Nevertheless, the present studies declare active analogues like 7c, 7 l, 7a, 7j as leads. Work is ongoing in derivatizing active molecules to explore more effective leads as 15-LOX inhibitors as antiinflammatory agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The underlying correlation between the inflammation, innate immunity and cancer is extensively familiar and linked through a process mediated by three enzymes; cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP 450 ). The ever increase in the reported side effects of the antiinflammatory drugs against the targeted enzymes and the resistance developed afterwards compels the researchers to synthesize new effective molecules with safer profile. On the basis of these facts, our ongoing research on 1,3,4-oxadiazole derivatives deals with the synthesis of a new series of N-alkyl/aralky/aryl derivatives of 5-((p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-ylthio)acetamide (6a-o) which were developed by the sequential conversion of p-tolyloxyacetic acid (a) into ester (1) hydrazide (2) and 5-(p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-thiol (3). The designed compounds (6a-o) were acquired by the reaction of 1,3,4-oxadiazole (3) with numerous electrophiles (5a-o) in KOH. The synthesized analogues (6a-o) were characterized by FTIR, 1 H-, 13 C NMR spectroscopy, EI-MS and HR-EI-MS spectrometry, and were further assessed for their inhibitory potential against the soybean 15-LOX enzyme. The results showed excellent inhibitory potential of the compounds against the said enzyme, specifically 6o, 6b, 6n and 6e with inhibitory values (IC 50  ± SEM) of 21.5 ± 0.76, 24.3 ± 0.45, 29.1 ± 0.65 and 31.3 ± 0.78 µM, respectively. These compounds displayed < 55 % blood mononuclear cells (MNCs) cellular viability as measured by MTT assay at 0.25 mM concentration. Other compounds demonstrated moderate inhibitory activities with IC 50 values in the range of 33.2 ± 0.78 to 96.3 ± 0.73 µM and exhibited little cellular viability against MNCs except 6i, 6j, 6 m and 6 k that showed 61-79 % cellular viability. It was observed that most of the compounds (6o, 6b, 6n, 6e) were found more toxic towards MNCs at studied concentration of 0.25 mM. SAR studies revealed that the positions and nature of substituents accompanying phenyl ring have great influence on 15-LOX inhibitory activity. In the most active compound 6o, the amino acids Asp768 and Val126 were involved in hydrogen bonding, Thr529 was linked with π-anion interaction and π-sulphur interaction was displayed with Tyr525 and two π-alkyl interactions were formed with the benzene ring and amino acid residues Pro530 and Arg533. The in silico pharmacokinetics profiles and density functional theory calculations of the compounds further supported the in vitro findings. Further work on the synthesis of more oxadiazole derivatives is in progress in search for potential 'leads' for the drug discovery as LOX inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Leishmaniasis is the second and fourth highest cause of mortality and morbidity respectively among all tropical diseases. Recurrence in the onset of leishmaniasis is a major problem that needs to be addressed to reduce the case fatality rate and ensure timely clinical intervention. Here we are investigating the association of risk factors with recurrent cutaneous leishmaniasis to address this issue., Material and Methods: Patients received by Nasser Ullah Khan Babar Hospital in Peshawar, Pakistan from March 2019 to July 2020 were enrolled in this study. Those patients who developed symptoms after completion of treatment were included in Group-A while those who had atypical scars like leishmaniasis but were negative for cutaneous leishmaniasis were included in the comparison group tagged as Group B. All those individuals who had completed six weeks of treatment for CL but had normal complete blood counts (CBC) were included to avoid other underlying immunological pathologies, while we excluded those participants who had co-morbidities like diabetes, liver disease, cardiac disease, and pregnant and lactating women through their history Association was tested between Group-A and Group-B with other explanatory variables through chi-square test. The regression model was proposed to determine the predictors., Result: A total of 48 participants of both sexes were included in the study with a mean age of 32.2 ± 15.10. The data suggest that females are overrepresented among the patients with recurrent leishmaniasis [21(53.8 %,); p = 0.07]. Compared to patients; healthy participants had a higher proportion of adults (19-59 years) versus adolescents (13-18 years) [26(66.7 %) vs 07(17.9), p = 0.004]. Multivariate logistic regression analysis shows that females are 2.1 times more prone to infections among cases as compared to healthy individuals [unadjusted OR 2.20, 95 % confidence interval (CI) 1.5-10.6, p = 0.02; adjusted OR 2.1, 95 % CI 1.50-10.69, p = 0.02]. We propose that patients receiving intradermal were less likely to be infected as compared to those receiving intralesional injections [unadjusted OR 0.07.0, 95 % confidence interval (CI) 1.18-3.37, p = 0.03; adjusted OR 0.06, 95 % CI 1.18-3.38, p = 0.03]., Conclusion: Old age (adults) and sex (females) were the strongest predictors to be associated with recurrent leishmaniasis. Similarly, the choice of intradermal as compared to intralesional injection and the prolonged treatment duration were strongly associated with greater chances of recurrence., Competing Interests: Conflict of interest None declared., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Paxillin is one of the most important adapters in integrin-mediated adhesions that performs numerous crucial functions relying on its dynamic interactions. Its structural behavior serves different purposes, providing a base for several activities. The various domains of paxillin display different functions in the whole process of cell movements and have a significant role in cell adhesion, migration, signal transmission, and protein-protein interactions. On the other hand, some paxillin-associated proteins provide a unique spatiotemporal mechanism for regulating its dynamic characteristics in the tissue homeostasis and make it a more complex and decisive protein at the focal adhesions. This review briefly describes the structural adaptations and molecular mechanisms of recruitment of paxillin into adhesions, explains paxillin's binding dynamics and impact on adhesion stability and turnover, and reveals a variety of paxillin-associated regulatory mechanisms and how paxillin is embedded into the signaling networks., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Searching small molecules as an auspicious approach to develop new anti-inflammatory drugs is a challenge for the researchers especially by modifying active pharmacophoric groups in the targeted molecules. In the current work, a series of new S-alkyl/aralky derivatives (8a-h; 9a-h) of 2-(4-ethyl/phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazol-3-ylthio)ether were synthesized and assessed for their inhibitory action against the 15-lipoxygenase from soybean (15-sLOX). The basic precursor ethyl piperidine-4-carboxylate (a) was consecutively changed into phenylcarbamoyl derivative (1), hydrazide (2), semicarbazides (3/4) and N-ethyl/phenyl-5-(1-phenylcarbamoylpiperidine)-1,2,4-triazoles (5/6), which further in association with electrophiles (7a-h) promoted to the final products (8a-h; 9a-h). The synthesized derivatives were characterized by FT-IR, 1 H-, 13 C NMR spectroscopy, EI-MS, and HR-EI-MS spectrometry. Amongst these, 8a, 8c, and 9c, expressed potent inhibitory profiles against the 15-sLOX enzyme with IC 50 values of 12.52 ± 0.35 to 35.64 ± 0.29 µM, followed by the compounds 9b, 9g, 9d, 9a, 8b, 8e, 8d, 8g, 8h, 8f and 9h with IC 50 values in the range of 43.78 ± 0.43 to 108.65 ± 0.38 µM. All compounds exhibited variable cellular viability levels by MTT assay. Flow cytometric data demonstrated that 8f, 8g, 8h have maximal lymphocyte cellular viability and all compounds affected cells in the late apoptosis phase. In silico ADMET studies supported the drug-likeness of most of the molecules. These studies were supported by molecular docking against 15-sLOX, human 5-LOX (5-hLOX) and human 15-LOX (5-hLOX); that inhibitors of 15-sLOX docked-in the active pocket of either 5-hLOX or 15-hLOX and docking score remained constant for all three enzymes within a narrow range (-6.8 to -9.7) as did it for standard quercetin (-8.4 to -9.0). The most dominant bonding interactions were π-π, π-anion, and π-alkyl type along with the hydrogen bonding. The data collected altogether demonstrates the better possibility of some of these compounds as good LOX inhibitors in search for 'lead' as anti-inflammatory agents in the process of drug discovery and development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In search for new anti-inflammatory agents that inhibit the enzymes of arachidonic acid pathway as the drug targets, the present article describes the screening of 1,3,4-oxadiazole analogues against lipoxygenase (LOX) enzyme. The work is based on the synthesis of new N-alkyl/aralky/aryl derivatives (6a-o) of 2-(4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,3,4-oxadiazol-3-ylthio)acetamide which were obtained by the reaction of 1,3,4-oxadiazole (3) with various electrophiles (5a-o), in KOH. The synthesized analogues showed potent to moderate inhibitory activity against the soybean 15-LOX enzyme; especially 6g, 6b, 6a and 6l displayed the potent inhibitory potential with IC 50 values 7.15 ± 0.26, 9.32 ± 0.42, 15.83 ± 0.45 & 18.37 ± 0.53 µM, respectively, while excellent to moderate inhibitory profiles with IC 50 values in the range of 26.13-98.21 µM were observed from the compounds 6k, 6m, 6j, 6o, 6h, 6f, 6n and 6c. Most of the active compounds exhibited considerable cell viability against blood mononuclear cells (MNCs) at 0.25 mM by MTT assay except 6f, 6h, 6k and 6m which showed around 50% cell viability. Flow cytometry studies of the selected compounds 6a, 6j and 6n revealed that these caused 79.5-88.51% early apoptotic changes in MNCs compared with 4.26% for control quercetin at their respective IC 50 values. The relative expression of 5-LOX gene was monitored in MNCs after treatment with these three molecules and all down-regulated the enzyme activity. In silico ADME and molecular docking studies further supported these studies of oxadiazole derivatives and considered it as potential 'lead' compounds in drug discovery and development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hunting small molecules as anti-inflammatory agents/drugs is an expanding and successful approach to treat several inflammatory diseases such as cancer, asthma, arthritis, and psoriasis. Besides other methods, inflammatory diseases can be treated by lipoxygenase inhibitors, which have a profound influence on the development and progression of inflammation. In the present study, a series of new N-alkyl/aralky/aryl derivatives (7a-o) of 2-(4-phenyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide was synthesized and screened for their inhibitory potential against the enzyme 15-lipoxygenase. The simple precursor ethyl piperidine-4-carboxylate (a) was successively converted into phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and N-phenylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4), then in combination with electrophiles (6a-o) through further multistep synthesis, final products (7a-o) were generated. All the synthesized compounds were characterized by FTIR, 1 H, 13 C NMR spectroscopy, EIMS, and HREIMS spectrometry. Almost all the synthesized compounds showed excellent inhibitory potential against the tested enzyme. Compounds 7c, 7f, 7d, and 7g displayed potent inhibitory potential (IC 50 9.25 ± 0.26 to 21.82 ± 0.35 µM), followed by the compounds 7n, 7h, 7e, 7a, 7b, 7l, and 7o with IC 50 values in the range of 24.56 ± 0.45 to 46.91 ± 0.57 µM. Compounds 7c, 7f, 7d exhibited 71.5 to 83.5% cellular viability by MTT assay compared with standard curcumin (76.9%) when assayed at 0.125 mM concentration. In silico ADME studies supported the drug-likeness of most of the molecules. In vitro inhibition studies were substantiated by molecular docking wherein the phenyl group attached to the triazole ring was making a π-δ interaction with Leu607. This work reveals the possibility of a synthetic approach of compounds in relation to lipoxygenase inhibition as potential lead compounds in drug discovery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In the current research work, different N-(substituted-phenyl)-4-{(4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl}butanamides have been synthesized according to the protocol described in scheme 1. The synthesis was initiated by reacting various substituted anilines (1a-e) with 4-chlorobutanoyl chloride (2) in aqueous basic medium to give various electrophiles, 4-chloro-N-(substituted-phenyl)butanamides (3a-e). These electrophiles were then coupled with 1-[(E)-3-phenyl-2-propenyl]piperazine (4) in polar aprotic medium to attain the targeted N-(substituted-phenyl)-4-{(4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl}butanamides (5a-e). The structures of all derivatives were identified and characterized by proton-nuclear magnetic resonance ( 1 H NMR), carbon-nuclear magnetic resonance ( 13 C NMR) and Infra-Red (IR) spectral data along with CHN analysis. The in vitro inhibitory potential of these butanamides was evaluated against Mushroom tyrosinase, whereby all compounds were found to be biologically active. Among them, 5b exhibited highest inhibitory potential with IC 50 value of 0.013 ± 0.001 µM. The same compound 5b was also assayed through in vivo approach, and it was explored that it significantly reduced the pigments in zebrafish. The in silico studies were also in agreement with aforesaid results. Moreover, these molecules were profiled for their cytotoxicity through hemolytic activity, and it was found that except 5e, all other compounds showed minimal toxicity. The compound 5a also exhibited comparable results. Hence, some of these compounds might be worthy candidates for the formulation and development of depigmentation drugs with minimum side effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In the designed research work, a series of 2-furoyl piperazine based sulfonamide derivatives were synthesized as therapeutic agents to target the Alzheimer's disease. The structures of the newly synthesized compounds were characterized through spectral analysis and their inhibitory potential was evaluated against butyrylcholinesterase (BChE). The cytotoxicity of these sulfonamides was also ascertained through hemolysis of bovine red blood cells. Furthermore, compounds were inspected by Lipinki Rule and their binding profiles against BChE were discerned by molecular docking. The protein fluctuations in docking complexes were recognized by dynamic simulation. From our in vitro and in silico results 5c, 5j and 5k were identified as promising lead compounds for the treatment of targeted disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Keeping in mind the pharmacological importance of 2-aminothiazole and 1,2,4-triazole heterocyclic moieties, a series of novel ethylated bi-heterocyclic acetamide hybrids, 9a-p, was synthesized in a multi-step protocol. The structures of newly synthesized compounds were characterized by 1 H NMR, 13 C NMR, IR and EI-MS spectral studies. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against elastase and all these molecules were identified as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which revealed that, 9h, inhibited elastase competitively by forming an enzyme-inhibitor complex. The inhibition constants K i calculated from Dixon plots for this compound was 0.9 µM. The computational study was articulate with the experimental results and these ligands unveiled good binding energy values (kcal/mol). So, these molecules can be considered as promising medicinal scaffolds for the treatment of skin melanoma, wrinkle formation, uneven pigmentation, and solar elastosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The present research was designed for the selective synthesis of novel bi-heterocyclic acetamides, 9a-n, and their tyrosinase inhibition to overwhelm the problem of melanogenesis. The structures of newly synthesized compounds were confirmed by spectral techniques such as 1 H NMR, 13 C NMR, and EI-MS along with elemental analysis. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against tyrosinase and all these molecules were recognized as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which explored that compound, 9h, inhibited tyrosinase competitively by forming an enzyme-inhibitor complex. The inhibition constants K i calculated from Dixon plots for this compound was 0.0027 µM. The computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal/mol). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules can be pondered as nontoxic medicinal scaffolds for skin pigmentation and related disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Present work aimed to synthesize some unique bi-heterocyclic benzamides as lead compounds for the in vitro inhibition of urease enzyme, followed by in silico studies. These targeted benzamides were synthesized in good yields through a multi-step protocol and their structures were confirmed by IR, 1 H NMR, 13 C NMR, EI-MS and elemental analysis. The in vitro screening results showed that most of the ligands exhibited good inhibitory potentials against the urease. Chemo-informatics analysis envisaged that all these compounds obeyed the Lipinski's rule. Molecular docking results showed that 7h exhibited good binding energy value (-8.40 kcal/mol) and was bound within the active region of urease enzyme. From the present investigation, it was inferred that some of these potent urease inhibitors might serve as novel templates in drug designing., (Copyright © 2018 Elsevier Inc. All rights reserved.)