Development Of New Compounds Research Articles

Insight into the Isolation, Synthesis, and Structure-Activity Relationship of Piperine Derivatives for the Development of New Compounds: Recent Updates.

Currently, black pepper commands the leading position among all the spices as a spice of great commercial importance in all the world trade and finds its way into the dietary habits of millions of people worldwide. Black pepper is biologically known as Piper nigrum and contains piperine as the main active chemical constituent. This paper highlights various general methods for extracting piperine from the crude drug such as maceration extraction, hydrotropic extraction, accelerated solvent extraction, thin-layer chromatography, and extraction with ethanol & dichloromethane Ionic fluid-based ultrasonic-assisted extraction, etc. In this review, piperine and its analogs exhibit numerous pharmacological activities and synthetic schemes of insecticidal activity, anti-cancer activity, anti-inflammatory activity, anti-diabetic activity, anti-hyperlipidemic activity, antifungal activity, narcotic activity, etc. and its structure-activity relationship. The biochemistry of piperine has also been summarized in the presented article. This very exhaustive review details the complete information about piperine, its derivatives, and further processing. Furthermore, the current study summarises recent research that has linked piperine to its use as a treatment for a variety of ailments.

Abstract LBA050: Bioenergetic evaluation of Mito-compound Mito-Met as potent cytotoxic agents in gastric cancer

Abstract Gastric cancer (GC) kills around 800,000 people each year around the world, placing it among the deadliest types of cancer. The evolution of intestinal metaplasia is unknown, but there are different factors that are involved in its development, the diet rich in salt, the Epstein-Barr virus, Helicobacter pylori and a wide variety of genes that affect cell activity. Currently, surgical resection with chemotherapy is the main treatment with a 5-year survival of 30% that varies according to the metastatic extension. The mitochondria is now one of the therapeutic targets in the development of new compounds with anticancer capacity and it has been observed that metformin behaves as an insulin sensitizer at high concentrations, inhibiting the mitochondrial complex I. For this reason, Mito-metformin (Mito-Met) was designed, this is a mitochondrial analogue of metformin that is linked to the lipophilic alkyl triphenylphosphonium cation (TPP) with a mitochondrial effect 1000 times greater at low concentrations. In this study, the effects of Mito-Met were evaluated in two GC cell lines (AGS and KATO III) and in the healthy gastric epithelium cell line (HPSEC). Cell viability, cytotoxicity, colony formation and cell migration assays were performed. Also, it was evaluated whether Mito-Met had the potential to affect mitochondrial bioenergetics by evaluating the OCR oxygen consumption rate, ECAR extracellular acidity rate, glycolytic capacity and mitochondrial fuel oxidation in live cells in real time using the analyzer XFe24 extracellular flux from Seahorse Biosciences. A dose-time-dependent decrease in cell viability was observed with IC50 values of 2.9 µM, 19,3 µM and 22,1 µM in AGS, KATO and HPSEC cells, respectively. The results in clonogenic assay showed that Mito-Met strongly affected AGS with an IC50 of 11.7 uM and a greater impact was observed in HPSEC than in KATO III, with IC50 values of 31.8 uM and 3.6 x 103 uM, respectively. The results of the wound healing assay showed that Mito-Met has a significant time-dependent dose effect on metastasis. Mito-Met affects the mitocondrial bioenergetics, our results showed affectation of basal respiration, maximum respiration, ATP production and reserve capacity in both cell lines. Mito-Met decreased baseline OCR and stressed OCR in a dose-dependent manner in both GC cell lines. Mito-Met increased the metabolic potential in a dose-dependent manner of OCR in AGS, on the contrary, a dose-dependent decrease of ECAR was observed in KATO III. There was no change in HPSEC. These results show that Mito-Met is promising compound for treatment of GC. Citation Format: Giovanni A Lineros Franco, Yenny Bueno, Micael Hardy, Olivier Ouari, Julio C. Montoya-Villegas, Marcos López-Casilla, Sandra M. Sanabria-Barrera. Bioenergetic evaluation of Mito-compound Mito-Met as potent cytotoxic agents in gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA050.

Major Phytocannabinoids and Their Related Compounds: Should We Only Search for Drugs That Act on Cannabinoid Receptors?

The most important discoveries in pharmacology, such as certain classes of analgesics or chemotherapeutics, started from natural extracts which have been found to have effects in traditional medicine. Cannabis, traditionally used in Asia for the treatment of pain, nausea, spasms, sleep, depression, and low appetite, is still a good candidate for the development of new compounds. If initially all attention was directed to the endocannabinoid system, recent studies suggest that many of the clinically proven effects are based on an intrinsic chain of mechanisms that do not necessarily involve only cannabinoid receptors. Recent research has shown that major phytocannabinoids and their derivatives also interact with non-cannabinoid receptors such as vanilloid receptor 1, transient receptor ankyrin 1 potential, peroxisome proliferator-activated receptor-gamma or glitazone receptor, G55 protein-coupled receptor, and nuclear receptor, producing pharmacological effects in diseases such as Alzheimer’s, epilepsy, depression, neuropathic pain, cancer, and diabetes. Nonetheless, further studies are needed to elucidate the precise mechanisms of these compounds. Structure modulation of phytocannabinoids, in order to improve pharmacological effects, should not be limited to the exploration of cannabinoid receptors, and it should target other courses of action discovered through recent research.

Assessing the risk of resistance to cationic biocides incorporating realism-based and biophysical approaches.

The control of microorganisms is a key objective in disease prevention and in medical, industrial, domestic, and food-production environments. Whilst the effectiveness of biocides in these contexts is well-evidenced, debate continues about the resistance risks associated with their use. This has driven an increased regulatory burden, which in turn could result in a reduction of both the deployment of current biocides and the development of new compounds and formulas. Efforts to balance risk and benefit are therefore of critical importance and should be underpinned by realistic methods and a multi-disciplinary approach, and through objective and critical analyses of the literature. The current literature on this topic can be difficult to navigate. Much of the evidence for potential issues of resistance generation by biocides is based on either correlation analysis of isolated bacteria, where reports of treatment failure are generally uncommon, or laboratory studies that do not necessarily represent real biocide applications. This is complicated by inconsistencies in the definition of the term resistance. Similar uncertainties also apply to cross-resistance between biocides and antibiotics. Risk assessment studies that can better inform practice are required. The resulting knowledge can be utilised by multiple stakeholders including those tasked with new product development, regulatory authorities, clinical practitioners, and the public. This review considers current evidence for resistance and cross-resistance and outlines efforts to increase realism in risk assessment. This is done in the background of the discussion of the mode of application of biocides and the demonstrable benefits as well as the potential risks.

Pseurotin D Induces Apoptosis through Targeting Redox Sensitive Pathways in Human Lymphoid Leukemia Cells.

Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in many geographical regions of the world. Pseurotin D, a secondary metabolite of fungi, represents a group of bioactive natural products with a newly ascribed range of interesting biological activities. The purpose of this study was to bring new insights into the mechanism behind the effects of pseurotin D on MEC-1 cells as a representative CLL cell line, with a particular focus on selected signaling pathways important in the proliferation of cells and targeting mitochondrial metabolism. Our results showed that pseurotin D was able to significantly inhibit the proliferation of MEC-1 cells and arrested them in the G2/M cell cycle phase. In addition, pseurotin D was able to induce apoptosis. We found that all of these effects were associated with a change in mitochondrial membrane potential and the production of mitochondrial reactive oxygen species (ROS). We showed for the first time that pseurotin D suppresses MEC-1 cell proliferation and induces apoptotic cell death via induction of the collapse of the mitochondria respiratory chain and the ROS-related caspase pathway. Our results show the pseurotins family as promising compounds which could serve as a basis for the development of new compounds in the treatment of lymphoma.

Elucidating molecular mechanisms of two-dimensional chemical reactions

Elucidating molecular mechanisms of two-dimensional chemical reactions

Multicolor Phenylenediamine Carbon Dots for Metal-Ion Detection with Picomolar Sensitivity.

Carbon dots keep attracting attention in multidisciplinary fields, motivating the development of new compounds. Phenylenediamine C6H4(NH2)2 dots are known to exhibit colorful emission, which depends on size, composition, and the functional surface groups, forming those structures. While quite a few fabrication protocols have been developed, the quantum yield of phenylenediamine dots still does not exceed 50% owing to undesired fragment formation during carbonization. Here, we demonstrate that an ethylene glycol-based environment allows obtaining multicolor high-quantum-yield phenylenediamine carbon dots. In particular, a kinetic realization of solvothermal synthesis in acidic environments enhances carbonization reaction yield for meta phenylenediamine compounds and leads to quantum yields, exciting 60%. Reaction yield after the product’s purification approaches 90%. Furthermore, proximity of metal ions (Nd3+, Co3+, La3+) can either enhance or quench the emission, depending on the concentration. Optical monitoring of the solution allows performing an accurate detection of ions at picomolar concentrations. An atomistic model of carbon dots was developed to confirm that the functional surface group positioning within the molecular structure has a major impact on dots’ physicochemical properties. The high performance of new carbon dots paves the way toward their integration in numerous applications, including imaging, sensing, and therapeutics.

New Applications of Zirconium Phosphate Nanomaterials

ConspectusThe 2-D layers of the inorganic ion exchanger α-zirconium phosphate (Zr(HPO4)2·H2O, α-ZrP) make this compound particularly stable to low pH, high temperature, and ionizing radiation. Initially studied for its ion exchange properties, once the conditions for its synthesis in crystalline form was accomplished by James Stynes and Abraham Clearfield in 1964, numerous other types of studies and applications followed. Extensive studies in the 1960s and 1970s on the thermodynamics of ion exchange led to insights into the intercalation mechanism of this material. The Clearfield group solved the crystal structure in 1968 and refined it in 1977. Powder methods were pioneered by the Clearfield group to solve the structure of this type of materials. In 1968 Giulio Alberti reported means to prepare zirconium phosphonates expanding the chemistry of these layered compounds. New phases of ZrP were also discovered (e.g., γ, θ, λ, τ) and the applications ranged from heterogeneous catalysis to intercalation chemistry and solid-state proton conductors. Methods to exfoliate the layers of ZrP were developed in the 1990s as interest grew in new applications of these types of materials. For example, protein and enzyme intercalation was accomplished starting in the 1990s by the McLendon, Mallouk, and Kumar groups. In the early 2000s, the Colón group pioneered the use of the θ phase of ZrP for the direct intercalation of large inorganic metal complexes that could not be directly intercalated into the α phase. Initial studies in the Colón group ranged from applications of these directly intercalated ZrP derivatives in photophysics and photochemistry, amperometric biosensors, vapochromism, and vapoluminescence. Over the past decade, new applications of these materials have been developed in anticancer drug delivery and electrocatalysis of the oxygen evolution reaction (OER). ZrP has now proven to be a promising drug nanocarrier and its unique chemical microenvironment provided by the α-type layers and the interlayer space enhances catalytic activity for numerous types of reactions. Further elucidation of the catalytic active species under operando conditions as well as the chemical structure of drug-intercalated derivatives should provide new insights that will advance the design and development of new compounds with desired properties. The initial pioneering efforts of Clearfield and Alberti are being continued by numerous research groups providing new exciting areas of development on the chemistry of layered M(IV) phosphate and phosphonate compounds. In this Account we present the efforts of the Colón group during the past decade on studies of the applications of ZrP for anticancer drug delivery and electrocatalysis of the OER.

Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are severe neurodegenerative disorders that belong to a common disease spectrum. The molecular and cellular aetiology of the spectrum is a highly complex encompassing dysfunction in many processes, including mitochondrial dysfunction and oxidative stress. There is a paucity of treatment options aside from therapies with subtle effects on the post diagnostic lifespan and symptom management. This presents great interest and necessity for the discovery and development of new compounds and therapies with beneficial effects on the disease. Polyphenols are secondary metabolites found in plant-based foods and are well known for their antioxidant activity. Recent research suggests that they also have a diverse array of neuroprotective functions that could lead to better treatments for neurodegenerative diseases. We present an overview of the effects of various polyphenols in cell line and animal models of ALS/FTD. Furthermore, possible mechanisms behind actions of the most researched compounds (resveratrol, curcumin and green tea catechins) are discussed.

Updates on targeted therapies for acute myeloid leukaemia.

In the past few years research in the underlying pathogenic mechanisms of acute myeloid leukaemia (AML) has led to remarkable advances in our understanding of the disease. Cytogenetic and molecular aberrations are the most important factors in determining response to chemotherapy as well as long-term outcome, but beyond prognostication are potential therapeutic targets. Our increased understanding of the pathogenesis of AML facilitated by next-generation sequencing has spurred the development of new compounds in the treatment of AML, particularly the creation of small molecules that target the disease on a molecular level. Many of the hopeful predictions outlined in our AML review of 2018 are now therapeutic realities: gemtuzumab ozogamicin, venetoclax, FLT3 inhibitors (midostaurin, gilteritinib), IDH inhibitors (ivosidenib, enasidenib), CPX-351, glasdegib, oral decitabine, and oral azacitidine. Others may soon be (quizartinib, APR246 magrolimab, menin inhibitors). The wealth of positive data allows reconsideration of what might soon be new standards of care in younger and older patients with AML. In this review we give an overview of recently approved therapies in AML and address present and future research directions.

Variability of Beta-Lactam Broth Microdilution for Pseudomonas aeruginosa.

Antimicrobial susceptibility testing for Pseudomonas aeruginosa is critical to determine suitable treatment options. Commercial susceptibility tests are typically calibrated against the reference method, broth microdilution (BMD). Imprecision of MICs obtained by BMD for the same isolate on repeat testing is known to exist. Factors that impact the extent of variability include concentration of the inoculum, operator effects, contents of the media, inherent strain properties, and the testing process or materials. We evaluated the variability of BMD for antipseudomonal beta-lactams (aztreonam, cefepime, ceftazidime, meropenem, piperacillin-tazobactam, ceftazidime-avibactam, and ceftolozane-tazobactam) tested against a collection of P. aeruginosa isolates. Multiple replicate BMD tests were performed, and MICs were compared to assess reproducibility, including the impact of the inoculum and operator. Overall, essential agreement (EA) was ≥90% for all beta-lactams tested. Absolute agreement (AA) was as low as 70% for some beta-lactams. Variability from the inoculum and operators impacted the reproducibility of MICs. Piperacillin-tazobactam exhibited the highest degree of variability with 74% AA and 94% EA. The implications of MIC variability are extensive, as the MIC is essential for multiple facets of microbiology, such as the development of new compounds and susceptibility tests, dose optimization, and pharmacokinetic/pharmacodynamic (PK/PD) targets for individual patients.

Novel angucycline/angucyclinone family of natural products discovered between 2010 and 2020

Angucyclines/angucyclinones are a large group of polycyclic aromatic polyketides and their producers are widely distributed in nature. This family of natural products attracts great attention because of their diverse biological activities and unique chemical structures. With the development of synthetic biology and the exploitation of the actinomycetes from previously unexplored environments, angucyclines/angucyclinones-like natural products with new skeletons were continuously discovered, thus enriching the structural diversity of this family. In this review we summarize the new angucyclines/angucyclinones analogues discovered in the last decade (2010-2020) by using different strategies, such as changing cultivation conditions, genetic modification, genome mining, bioactivity-guided compound isolation, and fermentation of actinomycetes from underexplored environments. We also discuss the role of synthetic biology in the discovery and development of new compounds of the angucycline/angucyclinone family.

Identification of the optimal codons for acetolactate synthase from weeds: an in-silico study

Although various studies of codon usage bias have been reported in a broad spectrum of organisms, no studies to date have examined codon usage bias for herbicide target genes. In this study, we analysed codon usage patterns for the acetolactate synthase (ALS) gene in eight monocot weeds and one model monocot. The base composition at the third codon position follows C3 > G3 > T3 > A3. The values of the effective number of codons (ENC or Nc) indicate low bias, and ENC or Nc vs. GC3 plot suggests that this low bias is due to mutational pressure. Low codon adaptation index and codon bias index values further supported the phenomenon of low bias. Additionally, the optimal codons, along with over- and under-represented codons, were identified. Gene design using optimal codons rather than overall abundant codons produce improved protein expression results. Our results can be used for further studies, including eliciting the mechanisms of herbicide resistance (occurring due to elevation of gene expression levels) and the development of new compounds, their efficiency and risk assessment for herbicide resistance evolution.

Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance

Multiple drug resistance (MDR), referring to the resistance of cancer cells to a broad spectrum of structurally and mechanistically unrelated drugs across membranes, severely impairs the response to chemotherapy and leads to chemotherapy failure. Overexpression of ATP binding cassette (ABC) transporters is a major contributing factor resulting in MDR, which can recognize and mediate the efflux of diverse drugs from cancer cells, thereby decreasing intracellular drug concentration. Therefore, modulators of ABC transporter could be used in combination with standard chemotherapeutic anticancer drugs to augment the therapeutic efficacy. This review summarizes the recent advances of important cancer-related ABC transporters, focusing on their physiological functions, structures, and the development of new compounds as ABC transporter inhibitors.

Armeniaspirol A: a novel anti-Helicobacter pylori agent.

SummaryAntibiotic resistance in Helicobacter pylori has been growing worldwide with current treatment regimens. Development of new compounds for treatment of H. pylori infections is urgently required to achieve a successful eradication therapy in the future. Armeniaspirols, a novel class of natural products isolated from Streptomyces armeniacus, have been previously identified as antibacterial agents against Gram‐positive pathogens. In this study, we found that armeniaspirol A (ARM1) exhibited potent antibacterial activity against H. pylori, including multidrug‐resistant strains, with MIC range values of 4–16 μg ml‐1. The underlying mechanism of action of ARM1 against H. pylori involved the disruption of bacterial cell membranes. Also, ARM1 inhibited biofilm formation, eliminated preformed biofilms and killed biofilm‐encased H. pylori in a dose‐dependent manner. In a mouse model of multidrug‐resistant H. pylori infection, dual therapy with ARM1 and omeprazole showed efficient in vivo killing efficacy comparable to the standard triple therapy, and induced negligible toxicity against normal tissues. Moreover, at acidic pH 2.5, ARM1 exhibited a much more potent anti‐H. pylori activity than metronidazole. Thus, these findings demonstrated that ARM1 is a novel potent anti‐H. pylori agent, which can be developed as a promising drug lead for treatment of H. pylori infections.

Xanthine Scaffold: Available Synthesis Routes to Deliver Diversity by Derivatization

The functionalization of the skeletal systems of heterocycles represents a significant goal for the development of new compounds. The heterocyclic molecule xanthine (3,7-dihydro-1Hpurine- 2,6-dione) is a purine base with a bicyclic ring skeleton and four different nitrogen atoms, three of them are -NH groups. The principal derivatives are the well known natural methylxanthines (e.g., caffeine, theophylline and theobromine) that have prominent physiological effects at a very low dose. The natural methylated xanthines, theophylline, theobromine and caffeine, are present in different plants such as the tea, cocoa and coffee species. For this reason natural xanthines can be considered as bio-based and renewable starting materials; their use in organic synthesis is strongly recommended in order to carry out sustainable chemistry. Essentially, the xanthine scaffold led to the preparation of numerous compounds very attractive in the pharmaceutical field, and these drugs are commercialized for a wide range of biological activities. The scope of this mini-review is to consider the use of natural xanthines as starting material in chemical transformations carried out in organic solvents, without the intent to be exhaustive of all the synthetically chemical applications. More information on the chemical and electrochemical reactivity of this structural core in an organic solvent can be useful for the scientific community. The effectiveness of natural xanthines can be improved by modifying the structures of these already biologically active compounds.

Synthesis, structural analysis and corrosion inhibition application of a new indazole derivative on mild steel surface in acidic media complemented with DFT and MD studies

A great deal of consideration has been given to the development of new compounds having diverse functionality. In this report, a new indazole derivative bearing a nitro group, namely 2-(3-chloro-5-nitro-1H-indazol-1-yl) acetic acid (CNIA) was synthesized, characterized, and used as corrosion inhibitor for mild steel (MS) in 1.0 M HCl. A full characterization of the prepared compound was performed using single‐crystal XRD, FT-IR, and UV–vis measurements; its corrosion inhibition properties were experimentally evaluated by potentiodynamic polarization (PDP) curves as well as electrochemical impedance spectroscopy (EIS) measurements, and theoretically by Density Functional Theory (DFT) and molecular dynamics (MD) simulations. Scanning electron microscope (SEM) was used to examine the morphology of the corroded metal surface before and after the inhibition. The findings demonstrated that the application of CNIA significantly reduced the corrosion rates of MS. The corrosion inhibition ability of the synthesized compound was also identified at a lower concentration in all experiments, reaching a maximum of 89 % at 10−3 mol/L. The results of potentiodynamic polarization curves and electrochemical impedance spectroscopy (EIS) confirmed that CNIA could be categorized as a mixed type inhibitor with an increased polarization resistance at higher concentrations. Langmuir's adsorption isotherm was found to fit the adsorption of CNIA molecules on the MS surface. SEM photographs showed obvious less-corroded morphologies in the presence of the CNIA as compared to untreated MS surface. Theoretical calculations were proposed to explain the mechanism of the inhibition effect and found that it is due to the donor/acceptor properties of the inhibitor and its parallel disposition over the steel surface. The present compound could be a promising corrosion inhibitor for mild steel in HCl solutions, and showed a corrosion inhibition property that is superior to similar compounds.

Synthesis, Electronic Structure, and Physical Properties of Layered Oxypnictides Sr2ScCrAsO3 and Ba3Sc2Cr2As2O5.

New CrAs-based layered mixed-anion compounds Sr2ScCrAsO3 (SrScO-21113) and Ba3Sc2Cr2As2O5 (BaScO-32225) were synthesized, and their electronic structures and physical properties were investigated. The structures of these compounds comprise stacking of the anti-fluorite CrAs layer and perovskite-like SrScO or BaScO layers. The lattice constants of these compounds are relatively longer than those of the related compounds, such as BaCr2As2, owing to the insertion of a large perovskite blocking layer of SrScO/BaScO. While there are variations in the crystal structure of this system, such as 21113 and 32225, their chemical stability calculated by the first-principles calculations indicated that SrScO-21113 is energetically favorable compared to SrScO-32225. The formation energies of BaScO-32225 and BaScO-21113 are close to each other; in the experiment, while there was an indication of BaScO-21113 formation, only BaScO-32225 was formed as a single phase because of the low chemical stability of BaScO-21113. The partial density of states indicates that the majority of states are obtained from the 3d4-electrons of the Cr element hybridized modestly with p electrons at the Fermi energy. The magnetic properties of these compounds were paramagnetic, and they were different from related compounds, such as BaCr2As2, probably because of their long a-axis lengths. The temperature dependences of the electrical resistivities of both samples were in good agreement with the electronic band structure calculations. The variety of structures in the series of compounds with a CrAs layer results in different physical properties, and further development of new compounds may bring novel functionalities, such as superconductivity.

Research Domain Criteria (RDoC): A Perspective to Probe the Biological Background behind Treatment Efficacy in Depression.

Major Depressive Disorder(MDD) and its frequent partial response to antidepressants are a major health concern and therefore an important focus of research. Despite the efforts, MDD pathogenesis and the mechanisms of antidepressant action are only partially understood. In the last few years, the need of rethinking the classification of depressive disorders and psychiatric disorders, in general, has been suggested, in order to provide a nosology that reflects more closely the biological background associated with disease pathogenesis and its role/significance in treatment. The classification proposed by the National Institute of Mental Health (NIMH), namely the research domain criteria (RDoC), may represent a key framework to guide research in this direction. A literature search was performed on PubMed and Google Scholar databases in order to retrieve data regarding Antidepressants effects on specific RDoC constructs. Further, the targets of drugs of interest were identified through the Drug bank database, and their possible function within RDoC constructs was discussed. In this review, we summarize and discuss the significance of the results of pre-clinical and clinical studies investigating specific RDoC paradigms relevant to depressive phenotypes and antidepressant effects. The RDoC framework may facilitate a more specific use of antidepressants based on the individual's spectrum of symptoms and the development of new compounds that target specific depressive symptoms.

Development of new compound that facilitate motor function recovery after brain injury

Development of new compound that facilitate motor function recovery after brain injury