Investigations of Limeum Indicum Plant for Diabetes Mellitus and Alzheimer's Disease Dual Therapy: Phytochemical, GC-MS Chemical Profiling, Enzyme Inhibition, Molecular Docking and In-Vivo Studies.

Limeum indicum has been widely utilized in traditional medicine but no experimental work has been done on this herb. The primary objective of this study was to conduct a phytochemical analysis and assess the multifunctional capabilities of aforementioned plant in dual therapy for Alzheimer's disease (AD) and Type 2 diabetes (T2D). The phytochemical screening of ethanol, methanol extract, and their derived fractions of Limeum indicum was conducted using GC-MS, HPLC, UV-analysis and FTIR. The antioxidant capacity was evaluated by DPPH method. The inhibitory potential of the extracts/fractions against α-, ß-glucosidase acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoaminine oxidases (MAO-A & B) was evaluated. Results revealed that acetonitrile fraction has highest inhibitory potential against α-glucosidase (IC50=68.47±0.05 µg/mL), methanol extract against ß-glucosidase (IC50=91.12±0.07 µg/mL), ethyl acetate fraction against AChE (IC50=59.0±0.02 µg/mL), ethanol extract against BChE (28.41±0.01 µg/mL), n-hexane fraction against MAO-A (IC50=150.5±0.31 µg/mL) and methanol extract for MAO-B (IC50=75.95±0.13 µg/mL). The docking analysis of extracts\fractions suggested the best binding scores within the active pocket of the respective enzymes. During the in-vivo investigation, ethanol extract produced hypoglycemic effect (134.52±2.79 and 119.38±1.40 mg/dl) after 21 days treatment at dose level of 250 and 500 mg/Kg. Histopathological findings further supported the in-vivo studies.

Graphormer supervised de novo protein design method and function validation.

Protein design is central to nearly all protein engineering problems, as it can enable the creation of proteins with new biological functions, such as improving the catalytic efficiency of enzymes. One key facet of protein design, fixed-backbone protein sequence design, seeks to design new sequences that will conform to a prescribed protein backbone structure. Nonetheless, existing sequence design methods present limitations, such as low sequence diversity and shortcomings in experimental validation of the designed functional proteins. These inadequacies obstruct the goal of functional protein design. To improve these limitations, we initially developed the Graphormer-based Protein Design (GPD) model. This model utilizes the Transformer on a graph-based representation of three-dimensional protein structures and incorporates Gaussian noise and a sequence random masks to node features, thereby enhancing sequence recovery and diversity. The performance of the GPD model was significantly better than that of the state-of-the-art ProteinMPNN model on multiple independent tests, especially for sequence diversity. We employed GPD to design CalB hydrolase and generated nine artificially designed CalB proteins. The results show a 1.7-fold increase in catalytic activity compared to that of the wild-type CalB and strong substrate selectivity on p-nitrophenyl acetate with different carbon chain lengths (C2-C16). Thus, the GPD method could be used for the de novo design of industrial enzymes and protein drugs. The code was released at https://github.com/decodermu/GPD.

Synthesis, in vitro, and in silico studies of morpholine-based thiosemicarbazones as ectonucleotide pyrophosphatase/phosphodiesterase-1 and -3 inhibitors.

An extensive range of new biologically active morpholine based thiosemicarbazones derivatives 3a-r were synthesized, characterized by spectral techniques and evaluated as inhibitors of ENPP isozymes. Most of the novel thiosemicarbazones exhibit potent inhibition towards NPP1 and NPP3 isozymes. Compound 3 h was potent inhibitor of NPP1 with IC50 value of 0.55 ±â€¯0.02. However, the most powerful inhibitor of NPP3 was 3e with an IC50 value of 0.24 ±â€¯0.02. Furthermore, Lineweaver-Burk plot for compound 3 h against NPP1 and for compound 3e against NPP3 was devised through enzymes kinetics studies. Molecular docking and in silico studies was also done for analysis of interaction pattern of all newly synthesized compounds. The results were further validated by molecular dynamic (MD) simulation where the stability of conformational transformation of the best protein-ligand complex (3e) were justified on the basis of RMSD and RMSF analysis.

A flexible mixed-optimization with H∞ control for coupled twin rotor MIMO system based on the method of inequality (MOI)- An experimental study.

This article introduces a cutting-edge H∞ model-based control method for uncertain Multi Input Multi Output (MIMO) systems, specifically focusing on UAVs, through a flexible mixed-optimization framework using the Method of Inequality (MOI). The proposed approach adaptively addresses crucial challenges such as unmodeled dynamics, noise interference, and parameter variations. Central to the design is a two-step controller development process. The first step involves Nonlinear Dynamic Inversion (NDI) and system decoupling for simplification, while the second step integrates H∞ control with MOI for optimal response tuning. This strategy is distinguished by its adaptability and focus on balancing robust stability and performance, effectively managing the intricate cross-coupling dynamics in UAV systems. The effectiveness of the proposed approach is validated through simulations conducted in MATLAB/Simulink environment. Results demonstrated the efficiency of the proposed robust control approach as evidenced by reduced steady-state error, diminished overshoot, and faster system response times, thus significantly outperforming traditional control methods.

Quinoline-sulfonamides as a multi-targeting neurotherapeutic for cognitive decline: in vitro, in silico studies and ADME evaluation of monoamine oxidases and cholinesterases inhibitors.

Alzheimer's disease (AD) is a multifactorial irreversible neurological disorder with multiple enzymes involved. In the treatment of AD, multifunctional agents targeting cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have shown promising results. Herein, a series of novel quinoline-sulfonamides (a1-18) were designed and synthesized as a dual inhibitor of MAOs and ChEs. The in vitro results showed that compounds a5, a12, a11, and a6 exhibited the most potent compounds against specific enzymes. They had IC50 value 0.59 ± 0.04 for MAO-A, 0.47 ± 0.03 for MAO-B, 0.58 ± 0.05 for BChE and 1.10 ± 0.77 for AChE µM respectively. Furthermore, kinetic studies revealed that these compounds are competitive. Molecular docking studies enhanced the understanding of the in silico component, unveiling critical interactions, specifically the hydrogen bonding interaction, π-π, π-alkyl, π-amid and π-sulfur interactions between the ligand and enzymes. These findings suggest that compounds a5, a6, a11, a12, a15, and a18 may be potent multifunctional candidates for AD treatment.

Real-time fluorescent monitoring of phase I xenobiotic-metabolizing enzymes.

This article explores the intricate landscape of advanced fluorescent probes crafted for the detection and real-time monitoring of phase I xenobiotic-metabolizing enzymes. Employing state-of-the-art technologies, such as fluorescence resonance energy transfer, intramolecular charge transfer, and solid-state luminescence enhancement, this article unfolds a multifaceted approach to unraveling the dynamics of enzymatic processes within living systems. This encompassing study involves the development and application of a diverse range of fluorescent probes, each intricately designed with tailored mechanisms to heighten sensitivity, providing dynamic insights into phase I xenobiotic-metabolizing enzymes. Understanding the role of phase I xenobiotic-metabolizing enzymes in these pathophysiological processes, is essential for both medical research and clinical practice. This knowledge can guide the development of approaches to prevent, diagnose, and treat a broad spectrum of diseases and conditions. This adaptability underscores their potential clinical applications in cancer diagnosis and personalized medicine. Noteworthy are the trifunctional fluorogenic probes, uniquely designed not only for fluorescence-based cellular imaging but also for the isolation of cellular glycosidases. This innovative feature opens novel avenues for comprehensive studies in enzyme biology, paving the way for potential therapeutic interventions. The research accentuates the selectivity and specificity of the probes, showcasing their proficiency in distinguishing various enzymes and their isoforms. The sophisticated design and successful deployment of these fluorescent probes mark significant advancements in enzymology, providing powerful tools for both researchers and clinicians. Beyond their immediate applications, these probes offer illuminating insights into disease mechanisms, facilitating early detection, and catalyzing the development of targeted therapeutic interventions. This work represents a substantial leap forward in the field, promising transformative implications for understanding and addressing complex biological processes. In essence, this research heralds a new era in the development of fluorescent probes, presenting a comprehensive and innovative approach that not only expands the understanding of cellular enzyme activities but also holds great promise for practical applications in clinical settings and therapeutic endeavors.

Compact rover surveying and laser scanning for BIM development.

This paper presents a custom made small rover based surveying, mapping and building information modeling solution. Majority of the commercially available mobile surveying systems are larger in size which restricts their maneuverability in the targeted indoor vicinities. Furthermore their functional cost is unaffordable for low budget projects belonging to developing markets. Keeping in view these challenges, an economical indigenous rover based scanning and mapping system has developed using orthogonal integration of two low cost RPLidar A1 laser scanners. All the instrumentation of the rover has been interfaced with Robot Operating System (ROS) for online processing and recording of all sensorial data. The ROS based pose and map estimations of the rover have performed using Simultaneous Localization and Mapping (SLAM) technique. The perceived class 1 laser scans data belonging to distinct vicinities with variable reflective properties have been successfully tested and validated for required structural modeling. Systematically the recorded scans have been used in offline mode to generate the 3D point cloud map of the surveyed environment. Later the structural planes extraction from the point cloud data has been done using Random Sampling and Consensus (RANSAC) technique. Finally the 2D floor plan and 3D building model have been developed using point cloud processing in appropriate software. Multiple interiors of existing buildings and under construction indoor sites have been scanned, mapped and modelled as presented in this paper. In addition, the validation of the as-built models have been performed by comparing with the actual architecture design of the surveyed buildings. In comparison to available surveying solutions present in the local market, the developed system has been found faster, accurate and user friendly to produce more enhanced structural results with minute details.

Nonlinear control of two-stage single-phase standalone photovoltaic system.

This paper presents a single-phase Photovoltaic (PV) inverter with its superior and robust control in a standalone mode. Initially, modeling and layout of the Buck-Boost DC-DC converter by adopting a non-linear Robust Integral Back-stepping controller (RIBSC) is provided. The controller makes use of a reference voltage generated through the regression plane so that the operating point corresponding to the maximum power point (MPP) could be achieved through the converter under changing climatic conditions. The other main purpose of the Buck-Boost converter is to act like a transformer and produce an increased voltage at the inverter input whenever desired. By not using a transformer makes the circuit size more compact and cost-effective. The proposed RIBSC is applied to an H-bridge inverter with an LC filter to produce the sinusoidal wave in the presence of variations in the output to minimize the difference between the output voltage and the reference voltage. Lyapunov stability criterion has been used to verify the stability and finite-time convergence of the overall system. The overall system is simulated in MATLAB/Simulink to test the system performance with different loads, varying climatic conditions and inverter reference voltages. The proposed methodology is compared with a back-stepping controller and Proportional Integral Derivative (PID) controller under rapidly varying climatic conditions. Results demonstrated that the proposed technique yielded a tracking time of 0.01s, a total harmonic distortion of 9.71% and a root means square error of 0.3998 in the case of resistive load thus showing superior control performance compared to the state-of-the-art control techniques.

Passivity-based Rieman Liouville fractional order sliding mode control of three phase inverter in a grid-connected photovoltaic system.

Photovoltaic (PV) system parameters are always non-linear due to variable environmental conditions. The Maximum power point tracking (MPPT) is difficult under multiple uncertainties, disruptions and the occurrence of time-varying stochastic conditions. Therefore, Passivity based Fractional order Sliding-Mode controller (PBSMC) is proposed to examine and develop a storage function in error tracking for PV power and direct voltage in this research work. A unique sliding surface for Fractional Order Sliding Mode Control (FOSMC) framework is proposed and its stability and finite time convergence is proved by implementing Lyapunov stability method. An additional input of sliding mode control (SMC) is also added to a passive system to boost the controller performance by removing the rapid uncertainties and disturbances. Therefore, PBSMC, along with globally consistent control efficiency under varying operating conditions is implemented with enhanced system damping and substantial robustness. The novelty of the proposed technique lies in a unique sliding surface for FOSMC framework based on Riemann Liouville (R-L) fractional calculus. Results have shown that the proposed control technique reduces the tracking error in PV output power, under variable irradiance conditions, by 81%, compared to fractional order proportional integral derivative (FOPID) controller. It is reduced by 39%, when compared to passivity based control (PBC) and 28%, when compared to passivity based FOPID (EPBFOPID). The proposed technique led to the least total harmonic distortion in the grid side voltage and current. The tracking time of PV output power is 0.025 seconds in PBSMC under varying solar irradiance, however FOPID, PBC, EPBFOPID, have failed to converge fully. Similarly the dc link voltage has tracked the reference voltage in 0.05 seconds however the rest of the methods either could not converge, or converged after significant amount of time. During solar irradiance and temperature change, the photovoltaic output power has converged in 0.018 seconds using PBSMC, however remaining methods failed to converge or track fully and the dc link voltage has minimum tracking error due to PBSMC as compared to the other methods. Furthermore, the photovoltaic output power converges to the reference power in 0.1 seconds in power grid voltage drop, whereas other methods failed to converge fully. In addition power is also injected from the PV inverter into the grid at unity power factor.

Adaptive optimal control of under-actuated robotic systems using a self-regulating nonlinear weight-adjustment scheme: Formulation and experimental verification.

This paper formulates an innovative model-free self-organizing weight adaptation that strengthens the robustness of a Linear Quadratic Regulator (LQR) for inverted pendulum-like mechatronic systems against perturbations and parametric uncertainties. The proposed control procedure is devised by using an online adaptation law to dynamically adjust the state weighting factors of LQR's quadratic performance index via pre-calibrated state-error-dependent hyperbolic secant functions (HSFs). The updated state-weighting factors re-compute the optimal control problem to modify the state-compensator gains online. The novelty of the proposed article lies in adaptively adjusting the variation rates of the said HSFs via an auxiliary model-free online self-regulation law that uses dissipative and anti-dissipative terms to flexibly re-calibrate the nonlinear function's waveforms as the state errors vary. This augmentation increases the controller's design flexibility and enhances the system's disturbance rejection capacity while economizing control energy expenditure under every operating condition. The proposed self-organizing LQR is analyzed via customized hardware-in-loop (HIL) experiments conducted on the Quanser's single-link rotational inverted pendulum. As compared to the fixed-gain LQR, the proposed SR-EM-STC delivers an improvement of 52.2%, 16.4%, 55.2%, and 42.7% in the pendulum's position regulation behavior, control energy expenditure, transient recovery duration, and peak overshoot, respectively. The experimental outcomes validate the superior robustness of the proposed scheme against exogenous disturbances.

Investigation of vibration's effect on driver in optimal motion cueing algorithm.

The increased sensation error between the surroundings and the driver is a major problem in driving simulators, resulting in unrealistic motion cues. Intelligent control schemes have to be developed to provide realistic motion cues to the driver. The driver's body model incorporates the effects of vibrations on the driver's health, comfort, perception, and motion sickness, and most of the current research on motion cueing has not considered these factors. This article proposes a novel optimal motion cueing algorithm that utilizes the driver's body model in conjunction with the driver's perception model to minimize the sensation error. Moreover, this article employs H∞ control in place of the linear quadratic regulator to optimize the quadratic cost function of sensation error. As compared to state of the art, we achieve decreased sensation error in terms of small root-mean-square difference (70%, 61%, and 84% decrease in case of longitudinal acceleration, lateral acceleration, and yaw velocity, respectively) and improved coefficient of cross-correlation (3% and 1% increase in case of longitudinal and lateral acceleration, respectively).

[1, 8]-Naphthyridine derivatives as dual inhibitor of alkaline phosphatase and carbonic anhydrase.

[1,8]-Naphthyridine derivatives have been reported to possess important biological activities and may serve as attractive pharmacophores in the drug discovery process. [1,8]-Naphthyridine derivatives (1a-1l) were evaluated for inhibitory potential for isozymes of carbonic anhydrase (CA) and alkaline phosphatase (ALP). CAs have been reported to carry out reversible hydration of CO2 into HCO3-, secretion of electrolytes, acid-base regulation, bone resorption, calcification, and biosynthetic reactions. Whereas ALPs hydrolyze monophosphate esters with the release of inorganic phosphate and play an important role in bone mineralization. Both enzymes have been found to be over-expressed and raised functional activities in patients suffering from rheumatoid arthritis. The discovery of dual inhibitors of these enzymes may provide a synergistic effect to cure bone disorders such as rheumatoid arthritis and ankylosing spondylitis. Among the test compounds, the most potent inhibitors for CA-II, CA-IX, and CA-XII were 1e, 1g, and 1a with IC50 values of 0.44 ± 0.19, 0.11 ± 0.03 and 0.32 ± 0.07 µM, respectively. [1,8]-Naphthyridine derivatives (1a-1l) were approximately 4 folds more potent than standard CA inhibitor acetazolamide. While in the case of ALPs, the most potent compounds for b-TNAP and c-IAP were 1b and 1e with IC50 values of 0.122 ± 0.06 and 0.107 ± 0.02 µM, respectively. Thus, synthesized derivatives proved to be 100 to 800 times more potent as compared to standard inhibitors of b-TNAP and c-IAP (Levamisole and L-phenyl alanine, respectively). In addition, selectivity and dual inhibition of [1,8]-Naphthyridine derivatives confer precedence over known inhibitors. Molecular docking and molecular simulation studies were also conducted in the present studies to define the type of interactions between potential inhibitors and enzyme active sites.

Evaluation of synthetic aminoquinoline derivatives as urease inhibitors: in vitro, in silico and kinetic studies.

Background: Quinoline and acyl thiourea scaffolds have major chemical significance in medicinal chemistry. Quinoline-based acyl thiourea derivatives may potentially target the urease enzyme. Materials & methods: Quinoline-based acyl thiourea derivatives 1-26 were synthesized and tested for urease inhibitory activity. Results: 19 derivatives (1-19) showed enhanced urease enzyme inhibitory potential (IC50 = 1.19-18.92 µM) compared with standard thiourea (IC50 = 19.53 ± 0.032 µM), whereas compounds 20-26 were inactive. Compounds with OCH3, OC2H5, Br and CH3 on the aryl ring showed significantly greater inhibitory potential than compounds with hydrocarbon chains of varying length. Molecular docking studies were conducted to investigate ligand interactions with the enzyme's active site. Conclusion: The identified hits can serve as potential leads against the drug target urease in advanced studies.

Essential Oil from Tagetes minuta Has Antiquorum Sensing and Antibiofilm Potential against Pseudomonas aeruginosa Strain PAO1.

Biofilms are complex communities of microorganisms that are enclosed in a matrix that shows increased resistance to antimicrobial and immunological encounters. Mostly, the traditional methods to control biofilm are exhausted; therefore, the aim is to evaluate the potential of essential oil (EO) from Tagetes minuta to encounter biofilm and other related virulence factors. The EO of T. minuta was extracted through steam-distillation, analyzed on gas chromatography-mass spectrometry, and the biofilm inhibition assays were performed with various concentrations of EO. Mainly the EO from T. minuta contains cis-ß-ocimene (29.1%), trans-tagetenone (23.1%), and cis-tagetenone (17.7%). The virulence factors were monitored while applying different concentrations of EO and it was recorded that the EO from T. minuta significantly inhibited the virulence factors linked with quorum sensing (QS), such as pyocyanin production, protease production, and swarming motility. Biofilm formation is one of the most important virulence factors associated with the QS pathway and was inhibited up to 79% in the presence of EO. Antibacterial activity against the PAO1 of EO was not so promising particularly and it has high MIC (325 µg/mL) and MBC (5000 µg/mL). EO is quite efficient to inhibit biofilm in a very small concentration of 20 µg/mL, which confirms that the biofilm inhibition by EO is not by killing bacterial cells but by inhibiting the QS pathway. The study on PAO1 constructs carrying various QS reported genes confirmed that the EO interferes with the QS pathway that ultimately controls various virulence factors caused by PAO1.

Phytochemical analysis, in vitro and in silico effects from Alstonia boonei De Wild stem bark on selected digestive enzymes and adipogenesis in 3T3-L1 preadipocytes.

BACKGROUND: Obesity is a global health issue arising from the unhealthy accumulation of fat. Medicinal plants such as Alstonia boonei stem bark has been reported to possess body weight reducing effect in obese rats. Thus, this study sought to investigate the in vitro and in silico effects of fractions from Alstonia boonei stem bark on selected obesity-related digestive enzymes and adipogenesis in 3T3-L1 preadipocytes. METHOD: Two fractions were prepared from A. boonei: crude alkaloid fraction (CAF) and crude saponin fraction (CSF), and their phytochemical compounds were profiled using Liquid chromatography with tandem mass spectrometry (LCMS/MS). The fractions were assayed for inhibitory activity against lipase, α-amylase and α-glucosidase, likewise their antiadipogenic effect in 3T3-L1 adipocytes. The binding properties with the 3 enzymes were also assessed using in silico tools. RESULTS: Eleven alkaloids and six saponin phytochemical compounds were identified in the CAF and CSF using LCMS/MS. The CAF and CSF revealed good inhibitory activity against pancreatic lipase enzyme, but weak and good activity against amylase respectively while only CSF had inhibitory activity against α-glucosidase. Both fractions showed antiadipogenic effect in the clearance of adipocytes and reduction of lipid content in 3T3-L1 adipocytes. The LCMS/MS identified compounds (41) from both fractions demonstrated good binding properties with the 3 enzymes, with at least the top ten compounds having higher binding energies than the reference inhibitors (acarbose and orlistat). The best two docked compounds to the three enzymes were firmly anchored in the substrate binding pockets of the enzymes. In a similar binding pattern as the reference acarbose, Estradiol-17-phenylpropionate (-11.0 kcal/mol) and 3α-O-trans-Feruloyl-2 α -hydroxy-12-ursen-28-oic acid (-10.0 kcal/mol) interacted with Asp197 a catalytic nucleophile of pancreatic amylase. Estradiol-17-phenylpropionate (-10.8 kcal/mol) and 10-Hydroxyyohimbine (-10.4 kcal/mol) interacted with the catalytic triad (Ser152-Asp176-His263) of pancreatic lipase while Estradiol-17-phenylpropionate (-10.1 kcal/mol) and 10-Hydroxyyohimbine (-9.9 kcal/mol) interacted with Asp616 and Asp518 the acid/base and nucleophilic residues of modelled α-glucosidase. CONCLUSION: The antiobesity effect of A. boonei was displayed by both the alkaloid and saponin fractions of the plant via inhibition of pancreatic lipase and adipogenesis.

Synthesis of new class of indole acetic acid sulfonate derivatives as ectonucleotidases inhibitors.

Ectonucleotidases inhibitors (ENPPs, e5'NT (CD73) and h-TNAP) are potential therapeutic candidates for the treatment of cancer. Adenosine, the cancer-developing, and growth moiety is the resultant product of these enzymes. The synthesis of small molecules that can increase the acidic and ionizable structure of adenosine 5-monophosphate (AMP) has been used in traditional attempts to inhibit ENPPs, ecto-5'-nucleotidase and h-TNAP. In this article, we present a short and interesting method for developing substituted indole acetic acid sulfonate derivatives (5a-5o), which are non-nucleotide based small molecules, and investigated their inhibitory potential against recombinant h-ENPP1, h-ENPP3, h-TNAP, h-e5'NT and r-e5'NT. Their overexpression in the tumor environment leads to high adenosine level that results in tumor development as well as immune evasion. Therefore, selective, and potent inhibitors of these enzymes would be expected to decrease adenosine levels and manage tumor development and progression. Our intended outcome led to the discovery of new potent inhibitors like' 5e (IC50 against h-ENPP1 = 0.32 ± 0.01 µM, 58 folds increased with respect to suramin), 5j (IC50 against h-ENPP3 = 0.62 ± 0.003 µM, 21 folds increase with respect to suramin), 5c (IC50 against h-e5'NT = 0.37 ± 0.03 µM, 115 folds increase with respect to sulfamic acid), 5i (IC50 against r-e5'NT = 0.81 ± 0.05 µM, 95 folds increase with respect to sulfamic acid), and 5g (IC50 against h-TNAP = 0.59 ± 0.08 µM, 36 folds increase with respect to Levamisole). Molecular docking studies revealed that inhibitors of these selected target enzymes induced favorable interactions with the key amino acids of the active site, including Lys255, Lys278, Asn277, Gly533, Lys528, Tyr451, Phe257, Tyr340, Gln465, Gln434, Lys437, Glu830, Cys818, Asn499, Arg40, Phe417, Phe500, Asn503, Asn599, Tyr281, Arg397, Asp526, Phe419 and Tyr502. Enzyme kinetic studies revealed that potent compounds such as 5j and 5e blocked these ectonucleotidases competitively while compounds 5e and 5c presented an un-competitive binding mode. 5g revealed a non-competitive mode of inhibition.

2-Oxoquinoline-based-thiosemicarbazones as multitargeting neurotherapeutics against Alzheimer's disease: In vitro and in silico studies of MAO and ChE inhibitors.

Alzheimer's disease (AD) presents a multifactorial neurological disorder with multiple enzyme involvement in its onset. Conventional monotherapies fall short in providing long-term relief, necessitating the exploration of alternative multitargeting approaches to address the complexity of AD. Therefore, the design, synthesis, and in vitro and in silico evaluation of 2-oxoquinoline-based thiosemicarbazones 9a-r as multipotent analogs, able to simultaneously inhibit the cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of AD, are reported. In the in vitro experimental evaluation of MAO and ChE inhibition, all tested compounds demonstrated remarkable potency exhibiting nonselective inhibition of both MAO-A and MAO-B, and selective inhibition of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE), with 9d, 9j, and 9m evolving as lead compounds for MAO-A, MAO-B, and AChE, displaying IC50 values of 0.35 ± 0.92, 0.50 ± 0.02, and 0.25 ± 0.13 µM, respectively. Moreover, the kinetic studies revealed that all tested compounds inhibited all three enzymes through a competitive mode of inhibition. Furthermore, the molecular docking studies of the most active compounds revealed several crucial interactions, particularly hydrogen bonding interactions. These interactions were observed between the nitrogen and sulfur atoms of thiosemicarbazone and the nitrogen and oxygen atoms of the quinoline ring with various amino acids, suggesting the strong interactions of these compounds with the enzymes.

Synthesis and biological evaluation of carboxamide and quinoline derivatives as P2X7R antagonists.

P2X7 receptor (P2X7R) has a key role in different pathological conditions, importantly overexpressed and activated in cancers. We explored the structure activity relationship (SAR) of three novel pyrazines, quinoline-carboxamide and oxadiazole series. Their selective inhibitory potency in Ca2+ mobilization assay using h-P2X7R-MCF-7 cells improved with phenyl ring substitutions (-OCF3, -CF3, and -CH3) in carboxamide and oxadiazole derivatives, respectively. However, highly electronegative fluoro, chloro, and iodo substitutions enhanced affinity. 1e, 2f, 2e, 1d, 2 g and 3e were most potent and selective toward h-P2X7R (IC50 values 0.457, 0.566, 0.624, 0.682, 0.813 and 0.890 µM, respectively) and were inactive at h-P2X4R, h-P2X2R, r-P2Y6R, h-P2Y2R, t-P2Y1R expressed in MCF-7 and 1321N1 astrocytoma cells. Cell viability (MTT assay at 100 µM, cell line) for 3e was 62% (HEK-293T), 70% (1321N1 astrocytoma) and 85% (MCF-7). >75% cell viability was noted for 2 g and >80% for 2e and 1d in all non-transfected cell lines. Anti-proliferative effects, compared to control (Bz-ATP), of selective antagonists (10 µM) were 3e (11%) 1d, (19%) 1e, (70%, P = 0.005) and 2f, (24%), indicating involvement of P2X7R. Apoptotic cell death by flow cytometry showed 1e to be most promising, with 35% cell death (PI positive cells), followed by 2e (25%), 2f (20%), and 1d (19%), compared to control. Fluorescence microscopic analysis of apoptotic changes in P2X7R-transfected cell lines was established. 1e and 2f at 1X and 2X IC50 increased cellular shrinkage, nuclear condensation and PI/DAPI fluorescence. In-silico antagonist modeling predicted ligand receptor interactions, and all compounds obeyed Lipinski rules. These results suggest that pyrazine, quinoline-carboxamide and oxadiazole derivatives could be moderately potent P2X7R antagonists for in vivo studies and anti-cancer drug development.

Modelling and robust controller design for an underactuated self-balancing robot with uncertain parameter estimation.

A comprehensive literature review of self-balancing robot (SBR) provides an insight to the strengths and limitations of the available control techniques for different applications. Most of the researchers have not included the payload and its variations in their investigations. To address this problem comprehensively, it was realized that a rigorous mathematical model of the SBR will help to design an effective control for the targeted system. A robust control for a two-wheeled SBR with unknown payload parameters is considered in these investigations. Although, its mechanical design has the advantage of additional maneuverability, however, the robot's stability is affected by changes in the rider's mass and height, which affect the robot's center of gravity (COG). Conventionally, variations in these parameters impact the performance of the controller that are designed with the assumption to operate under nominal values of the rider's mass and height. The proposed solution includes an extended Kalman filter (EKF) based sliding mode controller (SMC) with an extensive mathematical model describing the dynamics of the robot itself and the payload. The rider's mass and height are estimated using EKF and this information is used to improve the control of SBR. Significance of the proposed method is demonstrated by comparing simulation results with the conventional SMC under different scenarios as well as with other techniques in literature. The proposed method shows zero steady state error and no overshoot. Performance of the conventional SMC is improved with controller parameter estimation. Moreover, the stability issue in the reaching phase of the controller is also solved with the availability of parameter estimates. The proposed method is suitable for a wide range of indoor applications with no disturbance. This investigation provides a comprehensive comparison of available techniques to contextualize the proposed method within the scope of self-balancing robots for indoor applications.