Theoretical Insight into the Medicinal World of Organometallics: Macro versus Nano

Due to the unique physicochemical properties, organometallic complexes have been widely used in the medicinal world. These complexes have specific properties such as structural diversity, redox/catalytic activities, and possibility of ligand exchange. As the cancer therapies provided by these complexes are not always effective and have desired side effects, new treatment methods are needed for the successful therapies. Recent advances suggest that nanotechnology has also profound impact on the disease prevention, diagnosis, and treatment. The delivery system based on nanotechnology has faster drug absorption, controlled dosage release, and minimal side-effects. This technology is used for the treatment of cancer till now, but soon, it will find applications to other diseases also. The use of nanotechnology in the field of drug delivery is to develop a system that improves the solubility and bioavailability of hydrophobic drugs. It is used to increase specificity, developing delivery system for slow release, and to design delivery vehicles that can improve the circulatory presence of drugs. As the photophysics of organometallic complexes is still not clear, this topic is included to discuss the latest developments in this field, which allows the photochemical reactions at the nanolevel

Identification, analysis and inference of point mutations associated to drug resistance in bacteria: a lesson learnt from the resistance of Streptococcus pneumoniae to quinolones

Antibiotic resistance is one of the biggest public health challenges of our time. Bacterial chemoresistance is the phenomenon whereby bacteria develop the ability to survive and multiply in the presence of an antibacterial drug; the expression of a resistant phenotype may be due to three fundamental mechanisms, including the expression of enzymes that inactivate the antibacterial drug, changes in the membrane permeability to antibiotics and the onset of point mutations causing the physical-chemical alteration of the antimicrobial targets. In recent decades, new antibiotic resistance mechanisms have emerged and are spreading globally, threatening human health and the ability to fight the most common infectious diseases. Quinolones, a novel class of antibiotics that bind bacterial topoisomerases and inhibit cell replication, have been important in limiting the spread of penicillin- and macrolides-resistant Streptococcus pneumoniae. However, alarmingly, resistance to quinolones is spreading recently. Resistance is caused by the appearance of point mutations in the bacterial topoisomerase and gyrase. Some mutations are well known, but some are not and the information about known molecular mechanisms causing resistance is sparse and not systematically collected and organised. This means that it cannot be used to infer new mutations in newly sequenced bacterial genes and study how they may affect the drug binding. The lack of structured, organized, and reusable information about point mutations associated with antibiotic resistance represents a critical issue and is a common pattern in the field. Here, we present a structural analysis of point mutations involved in the resistance to quinolones affecting the gyrase and topoisomerase genes in Streptococcus pneumoniae. Results, extended to other bacterial species, have been collected in a database, Quinores3D db, and can now be used – through a web server, Quinores3D finder - to analyze both known and yet unknown mutations occurring in bacterial topoisomerases and gyrases. The development, testing and deployment of Quinores3D db and Quinores3D finder are further results of this PhD thesis. Furthermore, structural data about point mutations associated with antibiotic resistance were used to train, test and validate a machine learning algorithm for the inference of still unknown mutations potentially involved in bacterial resistance to quinolone. As the performance of the algorithm, measured in terms of accuracy, sensitivity and specificity, is very promising, we plan to incorporate it in the web server to allow users to predict new mutations associated with bacterial resistance to quinolones

Bioproducts for health II

In order to build a promising future, health and sustainability must be interelated. Marine, forestry, agriculture, and food systems are important sources of bioproducts used in health applications. To explore the potential of such sources for the development of natural products capable of biological activities, it is necessary to develop new technologically sustainable strategies. Despite the range of natural compounds already available, there is a need to identify bioactive molecules (e.g., polysaccharides, proteins and peptides, polyunsaturated fatty acids, and polyphenols) from different natural sources with positive health properties, including antihypertensive, antidiabetic, anti-obesity, antimicrobial, anti-atherosclerotic, antioxidant, antithrombotic, immune-modulatory, relaxing, and satiety-inducing effects. The Second Edition of this Special Issue aimed to identify and gather works on the latest varied sources of bioproducts, the biological and functional activities of these bioactive compounds, their mechanisms of action, and the methods used for extraction and purification, without losing our focus on alignment with the concept of green technology.info:eu-repo/semantics/publishedVersio

Novel Antibacterial Agents

This book was devoted to the latest advances achieved in the antibacterial field, with a focus on the recent efforts made to develop new antimicrobial agents with novel modes of action, and a perspective on future directions of this line of research. Antimicrobial resistance has become a major threat to global health, and the twenty-two published articles here reported put in evidence that the discovery and development of new antibiotics are extremely challenging. The antimicrobial research covers a wide area, spanning from the design of new compounds, also supported by molecular modeling techniques, their synthesis and characterization, and biological tests.In this context, the current crisis caused by the COVID-19 pandemic, but also older threats, such as the human immunodeficiency virus or the hepatitis C virus, require greater attention than ever.The research works described in this book provide an extremely useful example of the results achieved in the field of antibacterial drug development. The search for new chemical entities was approached starting from both natural and synthetic compounds and addressing different targets. In addition, recent findings were presented and discussed highlighting the strategies to fight bacterial resistance. Detailed references to the state-of-the-art can be found in this book.We strongly encourage the wide group of readers to explore the book that we are presenting, to get inspired to develop new approaches for the diagnosis and treatment of antibacterial diseases, and to circumvent resistance issues

New dose estimation methods and their application in early drug discovery using intravenous, oral and inhaled routes of administration for new chemical entities

Previously held under moratorium in Chemistry department (GSK) from 3 May 2019 until 18 June 2021.The pharmaceutical industry continues to face mounting fiscal, political and regulatory challenges developing the next generation of innovative medicines. Drug discovery scientists are directly challenged with the task of trying to overcome the challenge of poor R&D productivity by improving the quality of new chemical entities progressing into drug development to reduce drug attrition. This project focusses on early drug discovery and investigates the potential of a concept called Drug Efficiency (DE). DE was originally introduced by the Psychiatry CEDD (Centre of Excellence for Drug Discovery at GlaxoSmithKline) as an in vivo pharmacokinetic (PK) and PK-pharmacodynamic (PD) parameter to try and improve the quality of compounds progressing into in vivo PKPD models. The aim was to select compounds which would achieve higher free concentrations in the CNS, and therefore increase target engagement and improve efficacy. The focus of this project was to show how DE (and it’s in vitro biomimetic derived equivalent HPLC DEmax) can be used for projects involving intravenous (IV), oral and pulmonary routes of administration to select compounds with improved physicochemical properties (low MW, lipophilicity and solubility) and therefore more likely to have a low efficacious clinical dose during early lead optimisation. The combination of HPLC DEmax and in vitro potency makes it possible to estimate a clinical dose that would result in an efficacious steady-state free concentration at the site of action. The influence of the potential discrepancies between the in vitro and a later stage in vivo DEmax, the whole blood potency, volume of distribution and clearance on the dose estimation has been investigated using data from a GSK programme profiled during lead optimisation. It was found that drug potency had the greatest influence on estimating the clinical dose. When the estimated dose was low, the impact of small changes in PK parameters such as the volume of distribution and clearance had less effect and typically did not affect compound ranking. For inhaled pulmonary drugs, the physicochemical and PK properties are often considered to be the opposite of drugs administered by the IV and oral routes. The biggest challenge in the design of inhaled drugs is achieving the optimum balance of lung retention and pharmacological duration of action without causing lung toxicity. Unlike extravascular drugs, where there have been multiple physicochemical analyses and concepts proposed to help select the right balance of properties for successful drug design, there are very few drug design concepts beyond solubility and permeability for inhaled drug design. This project shows how HPLC DEmax can be used as a third critical parameter alongside solubility and permeability to help design inhaled small molecules which have “intrinsic” lung retention, pharmacological duration of action and improved lung safety. Lung retention was measured for a set of small molecule JAK inhibitors, which all had similar solubility and permeability, but different intrinsic lung retention. It was found that compounds with drug efficiencies (DEmax) of around 1% had extended lung exposure. Introducing DEmax as an additional parameter has shown that biomimetic binding can provide further information to help identify compounds with the improved potential to become drug candidates with the desired lung residency when administered via the pulmonary route.The pharmaceutical industry continues to face mounting fiscal, political and regulatory challenges developing the next generation of innovative medicines. Drug discovery scientists are directly challenged with the task of trying to overcome the challenge of poor R&D productivity by improving the quality of new chemical entities progressing into drug development to reduce drug attrition. This project focusses on early drug discovery and investigates the potential of a concept called Drug Efficiency (DE). DE was originally introduced by the Psychiatry CEDD (Centre of Excellence for Drug Discovery at GlaxoSmithKline) as an in vivo pharmacokinetic (PK) and PK-pharmacodynamic (PD) parameter to try and improve the quality of compounds progressing into in vivo PKPD models. The aim was to select compounds which would achieve higher free concentrations in the CNS, and therefore increase target engagement and improve efficacy. The focus of this project was to show how DE (and it’s in vitro biomimetic derived equivalent HPLC DEmax) can be used for projects involving intravenous (IV), oral and pulmonary routes of administration to select compounds with improved physicochemical properties (low MW, lipophilicity and solubility) and therefore more likely to have a low efficacious clinical dose during early lead optimisation. The combination of HPLC DEmax and in vitro potency makes it possible to estimate a clinical dose that would result in an efficacious steady-state free concentration at the site of action. The influence of the potential discrepancies between the in vitro and a later stage in vivo DEmax, the whole blood potency, volume of distribution and clearance on the dose estimation has been investigated using data from a GSK programme profiled during lead optimisation. It was found that drug potency had the greatest influence on estimating the clinical dose. When the estimated dose was low, the impact of small changes in PK parameters such as the volume of distribution and clearance had less effect and typically did not affect compound ranking. For inhaled pulmonary drugs, the physicochemical and PK properties are often considered to be the opposite of drugs administered by the IV and oral routes. The biggest challenge in the design of inhaled drugs is achieving the optimum balance of lung retention and pharmacological duration of action without causing lung toxicity. Unlike extravascular drugs, where there have been multiple physicochemical analyses and concepts proposed to help select the right balance of properties for successful drug design, there are very few drug design concepts beyond solubility and permeability for inhaled drug design. This project shows how HPLC DEmax can be used as a third critical parameter alongside solubility and permeability to help design inhaled small molecules which have “intrinsic” lung retention, pharmacological duration of action and improved lung safety. Lung retention was measured for a set of small molecule JAK inhibitors, which all had similar solubility and permeability, but different intrinsic lung retention. It was found that compounds with drug efficiencies (DEmax) of around 1% had extended lung exposure. Introducing DEmax as an additional parameter has shown that biomimetic binding can provide further information to help identify compounds with the improved potential to become drug candidates with the desired lung residency when administered via the pulmonary route

Quantitative structure-activity relationships: A biophysical, chemical and calorimetric study

Quantitative structure-activity relationships (QSAR) rationalize interrelation between molecular structure and biological response in terms of either physicochemical parameters, as in linear free energy relationships (LFER), or via purely empirical parameters, as is the case for De Novo schemes. In LFER the leading process is often the partitioning of a compound between two solvent phases, taken to represent the transfer of a drug molecule across a biological membrane. This study has investigated the partitioning behaviour of three series of hydroxybenzoate esters, viz. o-, m- and predominantly p-esters, the latter being preservatives in pharmaceutical formulations. The thermodynamic parameters AH, AG and AS for the transfer process were derived in an attempt to establish a QSAR. on a fundamental thermodynamic basis. Such parameters have identifiable physicochemical meaning and lend themselves more readily to interpretation. This facilitates application to alternative systems. A new Gibbs function factor analysis was developed and utilized to obtain thermodynamic contributions for parent and incremental methylene group portions of thestudy molecules. The empirical Collander equation for interrelation of various solute/solvent systems was also rationalized on a thermodynamic basis. Further extension of the Gibbs function factor analysis allowed scaling of "solvent" systems including chromatographic packings, solvents and liposomes. The scheme indicated capacity for optimized selection of bulk solvent systems to mimic biological membranes. A novel analytical procedure for direct measurement of biological response was developed. The bioassay appeared capable of discrimination i) between the closely related structural homologues, ii) between gram-negative and gram-positive bacteria, and further, iii) between certain cell batches of the same bacteria type. Also, the bioassay demonstrated a Collander interrelation between the two bacteria types. Flow microcalorimetry was the technique employed to measure thermal response of respiring E. coli and Staph, aur. bacteria. The modification of biological response with drug concentration was quantitated and a log dose max term was derived for each homologue. The results indicated potential for a predictive, additive structure-activity scheme based on assessment of biological response (BR) direct rather than through f(BR) via physicochemical or empirical parameters.<p

Removal of pharmaceutically active compounds from water systems using freeze concentration / by Yuanyuan Shao.

In the last few years, there has been a growing concern in the occurrence of pharmaceutically active compounds in the aquatic environment. Just in Europe, more than 3000 prescription and non-prescription drugs are used by human and animals and more than 80 drugs have been detected in municipal wastewater treatment plant effluent, surface water, groundwater, and in a few isolated cases, in drinking water, some at alarmingly high concentrations. Although no known human health effects have been associated with exposure to drinking water containing trace concentrations of drug residues, there is concrete evidence that these drug residues could cause numerous adverse health effects on aquatic life, even at very low concentrations. Municipal wastewater treatment plant effluents have been identified as the major source of drug residues in surface waters. Conventional wastewater treatment systems cannot effectively remove pharmaceutically active compounds. The suitability of distinct wastewater treatment processes for the elimination of drug residues has not been studied. Freezing has been used successfully to treat various wastewaters. Application of freezing technology to purify water is based on the principle that when water freezes, ice crystals grow of pure water and impurities are rejected from the ice structure and become concentrated in the unfrozen liquid. Without addition of any chemicals, contaminants in a large volume of dilute wastewater can be effectively removed by freeze concentration. Objectives of this study are: 1) literature review of occurrence of pharmaceutically active compounds, treatment technologies and analytical methods; and 2) experimental study: evaluate the potential of the freeze concentration process for the removal of selected pharmaceutically active compounds, the effect of initial concentration of drug residues, freezing temperature and degree of freezing on the removal efficiency of pharmaceutically active compounds. Five drugs aspirin, ibuprofen, gemfibrozil, metoprolol and sulfamethoxazole were selected to investigate the removal efficiency of freeze concentration. Gas chromatograph-mass spectrometry and total organic carbon were used to quantify the drug concentrations in water samples. After first freezing cycle, ibuprofen and gemfibrozil were concentrated 2-3 times compared to the feed water and the concentration factors reached 12 after second freezing cycle. The total removal efficiency of the selected pharmaceutically active compounds was about 80% after one stage freeze concentration. Results indicated that aspirin degraded during the treatment; therefore, the concentration of aspirin was difficult to measure. Analysis of sample total organic carbon concentration indicated that about 84% and 92% removal efficiency was achieved for ibuprofen and gemfibrozil one stage freeze concentration. Approximately 99% impurity removal efficiency and around 60% volume reduction was observed in refrozen ice obtained from the first freezing. This research results indicated freeze concentration was effective and not sensitive to the natural of target pharmaceutically active compounds in the feed water. In addition, the analytical methodology for the determination of drug residues in complex environmental matrices is still evolving and it may takes years before the universally accepted methods are developed. The gas chromatograph-mass spectrometry method used by many researchers requires complex sample preparation, which could influence the accuracy of the analysis

Anti-angiogenic and toxicity effects of Derris trifoliata extract in zebrafish embryo

Introduction: Derris trifoliata has been traditionally used as folk for the treatment of , rheumatic joints, diarrhoea, and dysmenorrhea, and rotenoids isolated from the plant have shown to exhibit anti-cancer properties. This study aimed to assess the toxicity effects and antiangiogenic activity of extract of Derris trifoliata on zebrafish embryo model. Materials and Methods: Zebrafihs embryos were treated with aqueous extract of Derris Trifoliata to evaluate its effects on angiogenesis and zebrafish-toxicity. Angiogenic response was analyzed using whole-mount alkaline phosphatase (AP) vessel staining on 72 hours post fertilization (hpf) zebrafish embryos. Results: 1.0 mg/ml concentration was toxic to zebrafish embryos and embryos exposed to concentrations at 0.5 mg/ml and below showed some malformations. Derris trifoliata aqueous extract also showed some anti-angiogenic activity in vivo in the zebrafish embryo model wereby at high concentration inhibited vessel formation in zebrafish embryo. Conclusions: The anti-angiogenic response of extract of Derris trifoliata in zebrafish in vivo model suggest its therapeutic potential as anti-cancer agent