Discovery Of Analogues Research Articles

Design and implementation of IMU-based locomotion mode recognition system on Zynq SoC

Active prostheses are becoming an increasingly viable option for lower limb amputees, as they can significantly improve their quality of life and mobility. However, to ensure a robust and effective control of these prostheses, the terrain environment must be considered. In this study, we have proposed a hardware implementation of a real-time low-latency human Locomotion Mode Recognition (LMR) system on a system on chip (SoC) platform from Xilinx, which can be customized and optimized based on the user's needs without requiring external computing resources or human intervention. The system uses a single IMU sensor placed on the shank, and includes all the stages in a LMR process, i.e. signal pre-processing, feature extraction, and terrains estimation using a MLP neural network classifier to classify five terrains (level walking, stair ascent/descent, ramp ascent/descent). To achieve a flexible and efficient hardware design, the proposed system architecture was optimized using parallelism and quantization optimization techniques. This approach has resulted in a significant performance improvement, with a processing speed 15 times faster than the PL non-optimized approach, and 4.3 times faster than the PS(-O3) optimized implementation on the same Zynq FPGA device. The proposed architecture was also validated in real time via the analog discovery device.

Fifty Years of Animal Toxin Research at the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS.

This review covers briefly the work carried out at our institute (IBCh), in many cases in collaboration with other Russian and foreign laboratories, for the last 50 years. It discusses the discoveries and studies of various animal toxins, including protein and peptide neurotoxins acting on the nicotinic acetylcholine receptors (nAChRs) and on other ion channels. Among the achievements are the determination of the primary structures of the α-bungarotoxin-like three-finger toxins (TFTs), covalently bound dimeric TFTs, glycosylated cytotoxin, inhibitory cystine knot toxins (ICK), modular ICKs, and such giant molecules as latrotoxins and peptide neurotoxins from the snake, as well as from other animal venoms. For a number of toxins, spatial structures were determined, mostly by 1H-NMR spectroscopy. Using this method in combination with molecular modeling, the molecular mechanisms of the interactions of several toxins with lipid membranes were established. In more detail are presented the results of recent years, among which are the discovery of α-bungarotoxin analogs distinguishing the two binding sites in the muscle-type nAChR, long-chain α-neurotoxins interacting with α9α10 nAChRs and with GABA-A receptors, and the strong antiviral effects of dimeric phospholipases A2. A summary of the toxins obtained from arthropod venoms includes only highly cited works describing the molecules' success story, which is associated with IBCh. In marine animals, versatile toxins in terms of structure and molecular targets were discovered, and careful work on α-conotoxins differing in specificity for individual nAChR subtypes gave information about their binding sites.

Multifrequency bioimpedance device based on the Analog Discovery 2: performance and characterization

Abstract Bioimpedance spectroscopy can be used to investigate the composition and monitor the human body, organs, tissues, or cell cultures by measuring the voltage developed by the injection of small alternating currents at different frequencies. These currents are injected sequentially through a frequency sweep and a with a Howland current source or one of its modifications. However, the frequency sweep is not time efficient and introduces problems with data coherence in the case of bioinstability. On the other hand, the Howland current source requires high precision matching between its components. In this contribution we developed a custom-made device for bioimpedance measurements based on a multisine current waveform and on a negative-feedback topology for the current source. Measurements on passive elements showed that the device had less than 1Ω and 0.05∘ uncertainty in the frequency range between 500 Hz and 200 kHz for impedance between 1 kΩ and 10 kΩ. The measurements were affected by an inductive artifact connected with the limited common-mode rejection at high frequencies. Nevertheless, we could characterize the artifacts through a fitting procedure to recover the expected value of the targeted impedance.

Synthesis and Structure-Activity Relationships of a New Class of Oxadiazoles Targeting DprE1 as Antitubercular Agents.

The continuing prevalence of drug-resistant tuberculosis threatens global TB control programs, highlighting the need to discover new drug candidates to feed the drug development pipeline. In this study, we describe a high-throughput screening hit (4-benzylpiperidin-1-yl)(1-(5-phenyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone (P1) as a potent antitubercular agent. Structure-activity guided synthesis led to the discovery of several analogs with high in vitro potency. P1 was found to have promising potency against many drug-resistant strains, as well as drug-susceptible clinical isolates. It also showed cidality against Mtb growing in host macrophages. Whole genome sequencing of genomic DNA from resistant mutants raised to P1 revealed mutations in decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1). This novel oxadiazole scaffold expands the set of chemical tools for targeting a well-validated pathway to treat tuberculosis.

Low-cost MRI System for Teaching.

Magnetic resonance imaging instrumentation is taught at Texas A&M University through the ECEN 463 course and its graduate level equivalent. This class guides students through several labs where they design their own desktop MRI system using various hardware components and LabVIEW. Because the system uses professional grade equipment, the cost of each lab station is high. As a result, there are only four lab stations available, which limits the class to 32 students. The equipment also contains parts that have become obsolete, inhibiting the ability to maintain the system long term. This project focuses on using easily accessible and more affordable equipment for the MRI system. It can also potentially provide opportunities for remote learning, where students could work on assignments off-campus. Other projects have aimed to design low-cost MRI systems with an emphasis on clinical applications or which require advanced FPGA programming skills or pre-programmed modules. This project will develop the MRI instrumentation with updated off-the-shelf components. The current equipment will be replaced with two Analog Discovery 2 devices, which are low-cost teaching tools. It will also feature inexpensive transmit and receive chains, off-the-shelf gradient amplifiers suitable for teaching, gradient coils for signal localization, and a lighter-weight Halbach magnet. In this stage of the project, projections and images have been captured using a 0.06T permanent magnet. In addition to validating successful system operation, each lab of the course will be integrated with current materials to comply with the new equipment. Hardware and software resources will also be prepared and scaled to meet classroom needs and ensure a smooth transition. The goal of the project is to use the new system starting in the fall 2023 semester.Clinical Relevance- This project shows that low-cost equipment can be implemented into a working MRI system. The intent for this project may be educationally focused, but it shows that extremely light and low-cost systems can be created. It may be reconstructed to have a deployable system that could be used in the field.

Discovery of triazole-bridged aryl adamantane analogs as an intriguing class of multifunctional agents for treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive brain disorder associated with slow loss of brain functions leading to memory failure and modest changes in behavior. The multifactorial neuropathological condition is due to a depletion of cholinergic neurons and accumulation of amyloid-beta (Aβ) plaques. Recently, a multi-target-directed ligand (MTDL) strategy has emerged as a robust drug discovery tool to overcome current challenges. In this research work, we aimed to design and develop a library of triazole-bridged aryl adamantane analogs for the treatment of AD. All synthesized analogs were characterized and evaluated through various in vitro and in vivo biological studies. The optimal compounds 32 and 33 exhibited potent inhibitory activities against acetylcholinesterase (AChE) (32 - IC50 = 0.086 μM; 33 - 0.135 μM), and significant Aβ aggregation inhibition (20 μM). N-methyl-d-aspartate (NMDA) receptor (GluN1-1b/GluN2B subunit combination) antagonistic activity of compounds 32 and 33 measured upon heterologous expression in Xenopus laevis oocytes showed IC50 values of 3.00 μM and 2.86 μM, respectively. The compounds possessed good blood-brain barrier permeability in the PAMPA assay and were safe for SH-SY5Y neuroblastoma (10 μM) and HEK-293 cell lines (30 μM). Furthermore, in vivo behavioral studies in rats demonstrated that both compounds improved cognitive and spatial memory impairment at a dose of 10 mg/kg oral administration. Together, our findings suggest triazole-bridged aryl adamantane as a promising new scaffold for the development of anti-Alzheimer's drugs.

Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy.

Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei, is one of the neglected tropical diseases with a continuing need for new medication. We here describe the discovery of 5-phenylpyrazolopyrimidinone analogs as a novel series of phenotypic antitrypanosomal agents. The most potent compound, 30 (NPD-2975), has an in vitro IC50 of 70 nM against T. b. brucei with no apparent toxicity against human MRC-5 lung fibroblasts. Showing good physicochemical properties, low toxicity potential, acceptable metabolic stability, and other pharmacokinetic features, 30 was further evaluated in an acute mouse model of T. b. brucei infection. After oral dosing at 50 mg/kg twice per day for five consecutive days, all infected mice were cured. Given its good drug-like properties and high in vivo antitrypanosomal potential, the 5-phenylpyrazolopyrimidinone analog 30 represents a promising lead for future drug development to treat HAT.

Discovery of berberine analogs as potent and highly selective p300/CBP HAT inhibitors

The protein p300 is a positive regulator of cancer progression and is related to many human pathological conditions. To find effective p300/CBP HAT inhibitors, we screened an internal compound library and identified berberine as a lead compound. Next, we designed, synthesized, and screened a series of novel berberine analogs, and discovered that analog 5d was a potent and highly selective p300/CBP HAT inhibitor with IC50 values of 0.070 μM and 1.755 μM for p300 and CBP, respectively. Western blotting further proved that 5d specifically decreased H3K18Ac and interfere with the function of histone acetyltransferase. Although 5d had only a moderate inhibitory effect on the MDA-MB-231 cell line, 5d suppressed the growth of 4T1 tumor growth in mice with a tumor weight inhibition ratio (TWI) of 39.7%. Further, liposomes-encapsulated 5d increased its inhibition of tumor growth to 57.8 % TWI. In addition, 5d has no obvious toxicity to the main organ of mice and the pharmacokinetic study confirmed that 5d has good absorption properties in vivo.

Discovery of novel phenyl triazole analogs as TRK/ALK dual inhibitors with prospective antitumor effects

The exploration of novel anaplastic lymphoma kinase (ALK) and tropomyosin receptor kinase (TRK) dual inhibitors tended to serve as targeted treatment of cancer. Herein, a series of phenyl triazole derivatives were designed and synthesized as ALK/TRK dual regulators based on structure-based drug design (SBDD) strategy and were evaluated for antiproliferative activity by MTT assay. Accordingly, all compounds showed surprising cytotoxicity with IC50 values below 10 μM on KM12, H2228 and KARPAS299 cell lines. Among them, compound 13a bearing (2-(4-methylpiperazin-1-yl)phenyl)morpholinomethanone moiety was identified as the optimal hit in enzymatic screening with IC50 values of 1.9 nM (TRKA), 7.2 nM (ALK) and 65.2 nM (ALKL1196M), respectively. Furthermore, 13a could inhibit KM12 cell migration and colony formation in a dose dependent manner. Meanwhile, AO/EB staining indicated that the pro-apoptotic effect of 13a was comparable to that of Entrectinib at the dose of 200 nM. Ultimately, the binding model of 13a with TRKA and ALK well established its mode of action which accounted for the superior activities as a promising antitumor candidate.

Discovery of seven-membered ring berberine analogues as highly potent and specific hCES2A inhibitors

Human carboxylesterase 2A (hCES2A) is a key serine hydrolase responsible for the metabolic clearance of large number of compounds bearing the ester- or amide-bond(s). Inhibition of hCES2A can relieve the chemotherapy-induced toxicity and alter the pharmacokinetic bahaviors of some orally administrate esters-containing agents. However, most of the hCES2A inhibitors show poor cell-membrane permeability and poor specificity. Herein, guided by the structure activity relationships (SAR) of fifteen natural alkaloids against hCES2A, fifteen new seven-membered ring berberine analogues were designed and synthesized, and their anti-hCES2A activities were evaluated. Among all tested compounds, compound 28 showed potent anti-hCES2A effect (IC50 = 1.66 μM) and excellent selectivity over hCES1A (IC50 > 100 μM). The SAR analysis revealed that the seven-membered ring of these berberine analogues was a crucial moiety for hCES2A inhibition, while the secondary amine group of the ring-C is important for improving their specificity over other serine hydrolases. Inhibition kinetic analyses and molecular dynamic simulation demonstrated that 28 strongly inhibited hCES2A in a mixed-inhibition manner, with an estimated Ki value of 1.035 μM. Moreover, 28 could inhibit intracellular hCES2A in living HepG2 cells and exhibited suitable metabolic stability. Collectively, the SAR of seven-membered ring berberine analogues as hCES2A inhibitors were studied, while compound 28 acted as a promising candidate for developing highly selective hCES2A inhibitors.

Development of Nystagmus Test and Measurement for Benign Paroxysmal Positional Vertigo

Vertigo is the illusion of rotation occuring due to a problem or a set of problems in the balance system of the body, and it is the situation that objects or places around the patients are in a revolving position around themselves. In vertigo, which is examined under two main headings as central and peripheral, central vertigo can be caused by aneurysms, tumors, and brain vascular distruption caused by brain lesions, while peripheral vertigo can occur due to thyroid types and metabolic disorders. Benign paroxysmal positional vertigo, colloquially called ‘crystal floating’, is the most common type of peripheral vertigo and many diagnostic, exercise and treatment methods are used in case of BPPV. However, today, as a result of the increase in computer use, treatment interactions have increased significantly. In line with the software created in this study, a computer-based diagnosis system and measurement system of nystagmus movements due to BPPV were developed. The system consists of three parts: mechanical, software and hardware. Visual Studio c# software interface and connection control software were formed in accordance with the diagnostic methods obtained from the literature. Software panels prepared on the interface for bithermal caloric and other tests are opened and the electronystagmography data prepared accordingly are graphed on Digilent Waveforms Analog Discovery. The performance of the BPPV test and measurement system were applied to the control group consisting of 10 healthy individuals. Dix-Hallpike, gaze, head rotation, optokinetic, pursuit tracking, bithermal caloric, Head Shaking and Saccadic tests were applied. As a result, the time for the preparation of the bithermal caloric test to 30-degree temperature value of the 3900 ml and 2600 ml was calculated as 4.00 ∓ 1.8 s and 3.67 ∓ 2.8 s. For 44-degree temperature value, they were -1,70 ∓ 2,75 s and -0,70 ∓ 3,09 s. Thus, it is seen that the developed system will enable the diagnosis of patients with BPPV to be determined in accordance with integrated visual stimuli in an accurate and ergonomic environment.

Discovery of Novel Bioactive Tanshinones and Carnosol Analogues against Breast Cancer.

The abietane diterpenoids ferruginol (1), tanshinone IIA (3), and carnosol (4) are well-known for their interesting pharmacological properties, including antitumor, similar to other natural and semisynthetic abietanes. In this study, a pair of semisynthetic C18-functionalized analogues of 3 and 4 were prepared from the commercially available (+)-dehydroabietylamine or readily obtained methyl dehydroabietate. Semisynthetic ferruginol (1) and some selected analogues, together with the synthesized analogues, were tested in vitro for the inhibition of proliferation in four breast cancer cell lines, SUM149, MDA-MB231, T47D, and MCF07. As a result, several tested abietane analogues decreased cell proliferation and enhanced cell death, with IC50 in the range 1.3-18.7 μM. This work demonstrates the antitumor activities of two tested compounds, making these molecules interesting for the development of new anticancer agents.

Discovery of pterostilbene analogs as novel NLRP3 inflammasome inhibitors for potential treatment of DSS-induced colitis in mice

The pterostilbene skeleton is a promising chemical scaffold that exerts anti-inflammatory, anti-depressant, and anti-tumor effects. In this study, we aim to reduce in vivo and in vitro toxicity of compound 32 (preliminary work) and maintain its biological activity. A series of novel pterostilbene derivatives (D1-D43) were designed and synthesized, and their anti-inflammatory activities were screened. All compounds were screened to evaluate their inhibitory effect on LPS/Nigericin-induced IL-1β production and pyroptosis. The structure–activity relationships was deduced, and finally 1-((E)-4-(2-ethoxyethoxy)styryl)-3,5-dimethoxy-2-((E)-2-nitrovinyl)benzene (D22) was found to be a low-toxic compound with most potent inhibitory efficacy (against IL-1β: IC50 = 2.41 μM). Preliminary mechanism studies showed that compound D22 may affect the assembly of NLRP3 inflammasome by targeting NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasome. The in vivo anti-inflammatory activity indicated that compound D22 had significant therapeutic effects on DSS-induced mouse acute colitis models.

Modifications in the piperazine ring of nucleozin affect anti-influenza activity.

The infection caused by the influenza virus is a latent tret. The limited access to vaccines and approved drugs highlights the need for additional antiviral agents. Nucleozin and its analogs have gain attention for their promising anti-influenza activity. To contribute to the advancement of the discovery and design of nucleozin analogs, we analyzed piperazine-modified nucleozin analogs to increase conformational freedom. Also, we describe a new synthetic strategy to obtain nucleozin and its analogues, three molecules were synthesized and two of them were biologically evaluated in vitro. Although the analogues were less active than nucleozin, the loss of activity highlights the need for the piperazine ring to maintain the activity of nucleozin analogs. Interestingly, this result agrees with the prediction of anti-influenza activity made with a QSAR model presented in this work. The proposed model and the synthetic route will be useful for the further development of nucleozin analogs with antiviral activity.

Low Energy Collision-Induced Dissociation of Azepine Pictet-Spengler Adducts of Nω-Methylserotonin.

Cimitrypazepines are a class of natural products produced by Pictet-Spengler condensation of Nω-methylserotonin and aldehydes in a manner that produces a seven-membered azepine ring. In this study, the fragmentation behavior of this class of molecules under low-energy CID was investigated in detail. Proposed mechanisms of fragmentation were supported by deuterium labeling and DFT calculations. Loss of methylamine and methylenimine were dominant fragmentation pathways of analogs containing an aliphatic side chain. Loss of methylenimine was found to proceed via unusual methyl cation transfer. Fragmentation of analogs containing an aromatic side chain was strongly influenced by the nature of the substituents and proceeded via a novel retro-Pictet-Spengler pathway and involvement of ion-neutral complexes. In some cases, a gas-phase interconversion between the azepine and β-carboline ring was observed during fragmentation. Detailed analysis of fragmentation behavior provided in this study will serve as a valuable guide for the discovery of new analogs from natural sources.

Novel Diarylthioether Compounds as Agents for the Treatment of Chagas Disease.

Herein, we describe the hit optimization of a novel diarylthioether chemical class found to be active against Trypanosoma cruzi; the parasite responsible for Chagas disease. The hit compound was discovered through a whole-cell phenotypic screen and as such, the mechanism of action for this chemical class is unknown. Our investigations led to clear structure-activity relationships and the discovery of several analogues with high in vitro potency. Furthermore, we observed excellent activity during acute in vivo efficacy studies in mice infected with transgenic T. cruzi. These diarylthioether compounds represent a promising new chemotype for Chagas disease drug discovery and merit further development to increase oral exposure without increasing toxicity.

Discovery of a potent olaparib-chlorambucil hybrid inhibitor of PARP1 for the treatment of cancer.

Introduction: Development of Poly (ADP-ribose) polymerase (PARP) inhibitors has been extensively studied in cancer treatment. Olaparib, the first approved PARP inhibitor, showed potency in the inhibition of both BRCA (breast cancer associated)-mutated and BRCA-unmutated cancers. Methods: Aiming to the discovery of olaparib analogs for the treatment of cancer, structural modifications were performed based on the scaffold of olaparib. In the first series, reduction of carbonyl group to CH2 led to decrease of PARP1 inhibitory activity. Preserving the original carbonyl group, molecules with potent PARP1 inhibitory activities were derived by introduction of hydrazide and aromatic nitrogen mustard groups. The synthesized compounds were evaluated in the in the PARP1 enzyme inhibitory screening, cancer cell based antiproliferative assay, cell cycle arrest and apoptosis studies. Results: It is remarkable that, molecule C2 with chlorambucil substitution, exhibited potent PARP1 inhibitory activity and a broad-spectrum of anticancer potency in the in vitro antiproliferative assay. Compared with olaparib and chlorambucil, molecule C2 also showed significant potency in inhibition of a variety of BRCA-unmutated cell lines. Further analysis revealed the effects of C2 in induction of G2/M phase cell cycle arrest and promotion of apoptosis. Discussion: Collectively, the olaparib-chlorambucil hybrid molecule (C2) could be utilized as a lead compound for further drug design.

Optimized electronic properties and nano-structural features for securing high thermoelectric performance in doped GeTe.

Recently, thermoelectric (TE) materials have been attracting great attention due to their improved capability to convert heat directly into electricity. PbTe-based TE materials are among the most competitive ones; however, lead toxicity limits their potential applications. Thus, the current focus in the field is on the discovery of lead-free analogues. GeTe is considered to be a promising candidate, however, its thermoelectric performance is limited by a non-ideal band structure and intrinsic Ge vacancies. In this work, GeTe was co-doped with Bi, Zn, and In. Initial doping with Bi enhances the performance by tuning the electronic properties and bringing down the thermal conductivity. Subsequent Zn doping permits to maintain the high power factor by increasing carrier mobility and reducing carrier concentration. Additionally, Zn incorporation lowers thermal conductivity and, thus, increases the performance. Subsequent In doping in (Ge0.97Zn0.02In0.01Te)0.97(Bi2Te3)0.03 reduces thermal conductivity even further and makes this material the best performing one. Scanning transmission electron microscopy shows the presence of nano twinning, defect layers, and dislocation bands that contribute to the suppression of the lattice thermal conductivity. A peak zT value of 2.06 and an average zT value of 1.30 have been achieved in (Ge0.97Zn0.02In0.01Te)0.97(Bi2Te3)0.03. These results are among the best state-of-the-art thermoelectric materials.

BIMMS: A versatile and portable system for biological tissue and electrode-tissue interface electrical characterization

The presented design is a low-cost, compact, and open-source USB-controlled platform for biological tissue and electrode-tissue interface electrical measurements, capable of potentiostatic and galvanostatic electrical impedance spectroscopy up to 10 MHz and cyclic voltammetry with voltage compliance of +−8 V and up to 2.4 mA while ensuring tissue-safety conditions. The data acquisition and generation are based on an Analog Discovery 2 platform (Digilent, USA). We provide accuracy analysis and comparisons with a commercially available calibrated impedance analyzer. Impedance measurements are demonstrated on implanted electrodes for neural stimulation and on an isolated ex-vivo calf brain as an example use case of the presented design.

Discovery and development of palmatine analogues as anti-NASH agents by activating farnesoid X receptor (FXR)

Sixty-one palmatine (PMT) derivatives, of which twenty-eight were new, were synthesized and evaluated for their anti-fibrogenic activities via collagen type I α 1 (COL1A1)-promoter based luciferase model in LX-2 cells, taking 2,3,10-trimethoxy-9-p-isopropyloxyprotopalmatine bromide (1) as the lead. Among them, compound 3a exerted the highest potency with the IC50 value of 8.19 μmol/L and SI value of 8.59, and reduced the expressions of multiple fibrogenic biomarkers, including COL1A1, TGF-β1, α-SMA and TIMP1 in a dose-dependent manner. In addition, it significantly reduced liver steatosis and inflammation, and especially attenuated the degree of liver fibrosis in choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD)-induced NASH mice model in vivo. Mechanism study indicated that it significantly ameliorated liver injury by activating farnesoid X receptor (FXR). BDL-induced fibrosis rats model further verified its liver-protective and anti-fibrosis activities. Therefore, PMT derivatives constituted a new family of non-steroidal FXR agonists as anti-NASH candidates, with the advantage of good safety profile, and are worthy for further investigation.