Synthesis, antimicrobial evaluation and QSAR studies of gallic acid derivatives

AbstractA series of gallic acid derivatives (1–33) was synthesized and characterized by physicochemical and spectral means. The synthesized compounds were evaluated in vitro for their antimicrobial activity against different Gram positive and Gram negative bacterial and fungal strains by the tube dilution method. Results of antimicrobial screening indicated that compound 6 was the most active antimicrobial agent (pMICam=1.92μM/mL). The results of QSAR studies demonstrated that antibacterial, antifungal and overall antimicrobial activities of synthesized gallic acid derivatives were governed by the electronic parameters, cosmic total energy (Cos E.) and nuclear energy (Nu. E.)

Modeling complex metabolic reactions, ecological systems, and financial and legal networks with MIANN models based on Markov-Wiener node descriptors

[Abstract] The use of numerical parameters in Complex Network analysis is expanding to new fields of application. At a molecular level, we can use them to describe the molecular structure of chemical entities, protein interactions, or metabolic networks. However, the applications are not restricted to the world of molecules and can be extended to the study of macroscopic nonliving systems, organisms, or even legal or social networks. On the other hand, the development of the field of Artificial Intelligence has led to the formulation of computational algorithms whose design is based on the structure and functioning of networks of biological neurons. These algorithms, called Artificial Neural Networks (ANNs), can be useful for the study of complex networks, since the numerical parameters that encode information of the network (for example centralities/node descriptors) can be used as inputs for the ANNs. The Wiener index (W) is a graph invariant widely used in chemoinformatics to quantify the molecular structure of drugs and to study complex networks. In this work, we explore for the first time the possibility of using Markov chains to calculate analogues of node distance numbers/W to describe complex networks from the point of view of their nodes. These parameters are called Markov-Wiener node descriptors of order kth (Wk). Please, note that these descriptors are not related to Markov-Wiener stochastic processes. Here, we calculated the Wk(i) values for a very high number of nodes (>100,000) in more than 100 different complex networks using the software MI-NODES. These networks were grouped according to the field of application. Molecular networks include the Metabolic Reaction Networks (MRNs) of 40 different organisms. In addition, we analyzed other biological and legal and social networks. These include the Interaction Web Database Biological Networks (IWDBNs), with 75 food webs or ecological systems and the Spanish Financial Law Network (SFLN). The calculated Wk(i) values were used as inputs for different ANNs in order to discriminate correct node connectivity patterns from incorrect random patterns. The MIANN models obtained present good values of Sensitivity/Specificity (%): MRNs (78/78), IWDBNs (90/88), and SFLN (86/84). These preliminary results are very promising from the point of view of a first exploratory study and suggest that the use of these models could be extended to the high-throughput re-evaluation of connectivity in known complex networks (collation)

Biological activities and ADMET-related properties of novel set of cinnamanilides

A series of nineteen novel ring-substituted N-arylcinnamanilides was synthesized and characterized. All investigated compounds were tested against Staphylococcus aureus as the reference strain, two clinical isolates of methicillin-resistant S. aureus (MRSA), and Mycobacterium tuberculosis. (2E)-N-[3-Fluoro-4-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide showed even better activity (minimum inhibitory concentration (MIC) 25.9 and 12.9 M) againstMRSAisolates than the commonly used ampicillin (MIC 45.8 M). The screening of the cell viability was performed using THP1-Blue NF- B cells and, except for (2E)-N-(4-bromo-3-chlorophenyl)-3-phenylprop-2-enamide (IC50 6.5 M), none of the discussed compounds showed any significant cytotoxic e ect up to 20 M. Moreover, all compounds were tested for their anti-inflammatory potential; several compounds attenuated the lipopolysaccharide-induced NF- B activation and were more potent than the parental cinnamic acid. The lipophilicity values were specified experimentally as well. In addition, in silico approximation of the lipophilicity values was performed employing a set of free/commercial clogP estimators, corrected afterwards by the corresponding pKa calculated at physiological pH and subsequently cross-compared with the experimental parameters. The similarity-driven property space evaluation of structural analogs was carried out using the principal component analysis, Tanimoto metrics, and Kohonen mapping

Immobilized artificial membrane chromatography: from medicinal chemistry to environmental sciences

Immobilized Artificial Membrane (IAM) chromatography constitutes a valuable tool for medicinal chemists to prioritize drug candidates in early drug development. The retention on IAM stationary phases encodes lipophilicity, electrostatic and other secondary interactions contrary to traditional octanol-water partitioning. An increasing number of publications in recent years have suggested that IAM indices, including isocratic log k(IAM) or extrapolated log kw(IAM) retention factors, chromatographic hydrophobicity index CHI(IAM) or the polarity parameter Δlog kw(IAM) can successfully model the passage of xeniobiotics through biological membranes and barriers and predict pharmacokinetic properties, often in combination with additional descriptors. Examples referring to the modeling of human oral absorption, blood-brain penetration and skin partition are described. More recently, IAM chromatography has been applied to estimate toxicological endpoints in regard to drug safety, such as phospholipidosis potential, or in regard to chemical risk hazards including the bioconcentration factor and aquatic organisms’ toxicity. The promising results in both medicinal chemistry and in environmental science in combination with the speed, reproducibility and low analyte consumption suggest that a broader application of IAM chromatography in the early drug discovery process and in ecotoxicity may save time and money in initial drug candidate selection and will contribute to a reduced risk hazard of chemicals

Exploring marine toxins: comparative analysis of chemical reactivity properties and potential for drug discovery

Marine toxins, produced by various marine microorganisms, pose significant risks to both marine ecosystems and human health. Understanding their diverse structures and properties is crucial for effective mitigation and exploration of their potential as therapeutic agents. This study presents a comparative analysis of two hydrophilic and two lipophilic marine toxins, examining their reactivity properties and bioavailability scores. By investigating similarities among these structurally diverse toxins, valuable insights into their potential as precursors for novel drug development can be gained. The exploration of lipophilic and hydrophilic properties in drug design is essential due to their distinct implications on drug distribution, elimination, and target interaction. By elucidating shared molecular properties among toxins, this research aims to identify patterns and trends that may guide future drug discovery efforts and contribute to the field of molecular toxinology. The findings from this study have the potential to expand knowledge on toxins, facilitate a deeper understanding of their bioactivities, and unlock new therapeutic possibilities to address unmet biomedical needs. The results showcased similarities among the studied systems, while also highlighting the exceptional attributes of Domoic Acid (DA) in terms of its interaction capabilities and stability

Challenges and solution approaches for an improved assessment of reproductive toxicity – species differences and in silico predictions

Within toxicology, reproductive toxicology is a highly relevant and socially particularly sensitive field. It encompasses all toxicological processes within the reproductive cycle and therefore includes many effects and modes of action. This makes the assessment of reproductive toxicity very challenging despite the established in vivo studies. In addition, the in vivo studies are very demanding both in terms of their conduct and interpretation, and there is scope for decision-making on both aspects. As a result, the interpretation of study results may vary from laboratory to laboratory. For the final classification, the assessment of relevance for men is decisive. The problem here is that relatively little is known about the species differences between men and the usual test animals (rat and rabbit). The rabbit in particular has hardly been researched in molecular biology. The aim of the dissertation was to develop approaches for a better assessment of reproductive toxicity, with two different foci: The first aim was to investigate species differences, focusing on the expression of xenobiotic transporters during ontogeny. Xenobiotic transporters, of the superfamily of ATP-binding cassette transporters (ABC) or solute carriers (SLC), are known to transport exogenous substances in addition to their endogenous substrates and therefore play an important role in the absorption, distribution and excretion of xenobiotics. Species differences in kinetics can in turn have a major impact on toxic effects. In the study, the expression of 20 xenobiotic transporters during ontogeny was investigated at the mRNA level in the liver, kidney and placenta of rats and rabbits and compared with that of men. This revealed major differences in the expression of the transporters between the species. However, further studies on the functionality and activity of the xenobiotic transporters are needed to fully assess the kinetic impact of the observed species differences. Overall, the study provides a valid starting point for further systematic investigations of species differences at the protein level. Furthermore, it provides previously unavailable data on the expression of xenobiotic transporters during ontogeny in rabbits, which is an important step in the molecular biological study of this species. The second part focused on investigating the predictive power of in silico models for reproductive toxicology in relation to pesticides. Both the commercial and the freely available models did not perform adequately in the evaluation. Three reasons could be identified for this: 1. many pesticides are outside the chemical space of the models, 2. different definition/assessment of reproductive toxicity and 3. problems in detecting similarity between molecules. To solve these problems, an extension of the databases on reproductive toxicity in relation to pesticides, respecting a uniform nomenclature, is needed. Furthermore, endpoint-specific models should be developed which, in addition to the usual structure-based fingerprints, use descriptors for, for example, biological activity. Overall, the dissertation shows how essential it is to further research the modes of action of reproductive toxicity. This knowledge is necessary to correctly assess in vivo studies and their relevance to men, as well as to improve the predictive power of in silico models by incorporating this information.Innerhalb der Toxikologie ist die Reproduktionstoxikologie ein hochrelevantes und gesellschaftlich besonders sensibles Fachgebiet. Sie umfasst alle toxikologischen Vorgänge innerhalb des Fortpflanzungszyklus und beinhaltet daher eine große Zahl an Effekten und Wirkmechanismen. Dies macht die Bewertung der Reproduktionstoxizität trotz der etablierten in vivo Studien sehr herausfordernd. Dazu kommt, dass die in vivo Studien sowohl bezogen auf ihre Durchführung als auch Interpretation sehr anspruchsvoll sind und es bei beiden Aspekten Entscheidungsspielräume gibt. Dies kann dazu führen, dass die Interpretation von Studienergebnissen von Labor zu Labor variiert. Für die abschließende Einstufung ist die Bewertung der Relevanz für den Menschen entscheidend. Problematisch dabei ist, dass relativ wenig über die Speziesunterschiede zwischen Menschen und den üblichen Versuchstieren (Ratte und Kaninchen) bekannt ist. Gerade das Kaninchen ist molekularbiologisch kaum erforscht. Ziel der Dissertation war es Lösungsansätze zur besseren Bewertung der Reproduktionstoxizität zu entwickeln, wobei zwei unterschiedlichen Schwerpunkte gesetzt wurden: Das erste Ziel war es, die Speziesunterschiede zu untersuchen, wobei der Schwerpunkt auf der Expression von xenobiotischen Transportern während der Ontogenese lag. Xenobiotische Transporter, der Superfamilie der ATP-bindenden Kassettentransporter (ABC) oder Solute Carrier (SLC), sind dafür bekannt, exogene Substanzen zusätzlich zu ihren endogenen Substraten zu transportieren und spielen daher eine wichtige Rolle bei der Absorption, Distribution und Exkretion von Xenobiotika. Speziesunterschiede in der Kinetik können wiederrum einen großen Einfluss auf die toxische Wirkung haben. In der Studie wurde die Expression von 20 xenobiotischen Transportern während der Ontogenese auf mRNA-Level in Leber, Niere und Plazenta von Ratten und Kaninchen untersucht und mit der des Menschen verglichen. Hierbei zeigten sich große Unterschiede in der Expression der Transporter zwischen den Spezies. Um die kinetischen Auswirkungen der beobachteten Artenunterschiede vollständig beurteilen zu können, sind jedoch weitere Studien zur Funktionalität und Aktivität der Fremdstofftransporter erforderlich. Insgesamt bietet die Studie einen validen Ausgangspunkt für weitere systematische Untersuchungen von Artenunterschieden auf Proteinebene. Darüber hinaus liefert sie bisher nicht verfügbare Daten zur Expression von xenobiotischen Transportern während der Ontogenese im Kaninchen, was einen wichtigen Schritt in der molekularbiologischen Untersuchung dieser Spezies darstellt. Im zweiten Teil lag der Schwerpunkt auf der Untersuchung der Vorhersagekraft von in silico Modellen für Reproduktionstoxikologie in Bezug auf Pestizide. Sowohl die kommerziellen als auch die frei verfügbaren Modelle schnitten bei der Bewertung nicht ausreichend ab. Dafür konnten drei Ursachen ausgemacht werden: 1. Viele Pestizide sind außerhalb des chemischen Raums der Modelle, 2. Unterschiedliche Definition/Beurteilung von Reproduktionstoxizität und 3. Probleme bei der Detektion von Ähnlichkeit zwischen Molekülen. Zur Lösung dieser Probleme ist eine Erweiterung der Datenbanken zur Reproduktionstoxizität in Bezug auf Pestizide, unter Beachtung einer einheitlichen Nomenklatur, nötig. Zudem sollten endpunktspezifische Modelle entwickelt werden, welche zusätzlich zu den üblichen strukturbasierten Fingerprints, Deskriptoren für zum Beispiel biologische Aktivität verwenden. Insgesamt zeigt die Dissertation, wie essenziell es ist, die Wirkmechanismen der Reproduktionstoxizität weiter zu erforschen. Dieses Wissen ist notwendig, um in vivo Studien und deren Relevanz für den Menschen korrekt zu beurteilen, sowie die Vorhersagekraft von in silico Modellen durch Einbeziehung dieser Informationen zu verbessern

Structure generation and de novo design using reaction networks

This project is concerned with de novo molecular design whereby novel molecules are built in silico and evaluated against properties relevant to biological activity, such as physicochemical properties and structural similarity to active compounds. The aim is to encourage cost-effective compound design by reducing the number of molecules requiring synthesis and analysis. One of the main issues in de novo design is ensuring that the molecules generated are synthesisable. In this project, a method is developed that enables virtual synthesis using rules derived from reaction sequences. Individual reactions taken from reaction databases were connected to form reaction networks. Reaction sequences were then extracted by tracing paths through the network and used to create ‘reaction sequence vectors’ (RSVs) which encode the differences between the start and end points of th esequences. RSVs can be applied to molecules to generate virtual products which are based on literature precedents. The RSVs were applied to structure-activity relationship (SAR) exploration using examples taken from the literature. They were shown to be effective in expanding the chemical space that is accessible from the given starting materials. Furthermore, each virtual product is associated with a potential synthetic route. They were then applied in de novo design scenarios with the aim of generating molecules that are predicted to be active using SAR models. Using a collection of RSVs with a set of small molecules as starting materials for de novo design proved that the method was capable of producing many useful, synthesisable compounds worthy of future study. The RSV method was then compared with a previously published method that is based on individual reactions (reaction vectors or RVs). The RSV approach was shown to be considerably faster than de novo design using RVs, however, the diversity of products was more limited

9th International Conference on Business, Technology and Innovation 2020

Welcome to IC – UBT 2020 UBT Annual International Conference is the 9th international interdisciplinary peer reviewed conference which publishes works of the scientists as well as practitioners in the area where UBT is active in Education, Research and Development. The UBT aims to implement an integrated strategy to establish itself as an internationally competitive, research-intensive university, committed to the transfer of knowledge and the provision of a world-class education to the most talented students from all background. The main perspective of the conference is to connect the scientists and practitioners from different disciplines in the same place and make them be aware of the recent advancements in different research fields, and provide them with a unique forum to share their experiences. It is also the place to support the new academic staff for doing research and publish their work in international standard level. This conference consists of sub conferences in different fields like: Security Studies Sport, Health and Society Psychology Political Science Pharmaceutical and Natural Sciences Mechatronics, System Engineering and Robotics Medicine and Nursing Modern Music, Digital Production and Management Management, Business and Economics Language and Culture Law Journalism, Media and Communication Information Systems and Security Integrated Design Energy Efficiency Engineering Education and Development Dental Sciences Computer Science and Communication Engineering Civil Engineering, Infrastructure and Environment Architecture and Spatial Planning Agriculture, Food Science and Technology Art and Digital Media This conference is the major scientific event of the UBT. It is organizing annually and always in cooperation with the partner universities from the region and Europe. We have to thank all Authors, partners, sponsors and also the conference organizing team making this event a real international scientific event. Edmond Hajrizi, President of UBTUBT – Higher Education Institutio