scholarly journals Synthesis, characterization and toxicity studies of pyridinecarboxaldehydes and L-tryptophan derived Schiff bases and corresponding copper (II) complexes

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1921 ◽  
Author(s):  
Margarita Malakyan ◽  
Nelly Babayan ◽  
Ruzanna Grigoryan ◽  
Natalya Sarkisyan ◽  
Vahan Tonoyan ◽  
...  
Keyword(s):  
Schiff Base ◽  
Drug Development ◽  
Schiff Bases ◽  
Copper Complexes ◽  
Development Process ◽  
Biological Activities ◽  
Drug Development Process ◽  
Relationship Analysis

Schiff bases and their metal-complexes are versatile compounds exhibiting a broad range of biological activities and thus actively used in the drug development process. The aim of the present study was the synthesis and characterization of new Schiff bases and their copper (II) complexes, derived from L-tryptophan and isomeric (2-; 3-; 4-) pyridinecarboxaldehydes, as well as the assessment of their toxicity in vitro. The optimal conditions of the Schiff base synthesis resulting in up to 75-85% yield of target products were identified. The structure-activity relationship analysis indicated that the location of the carboxaldehyde group at 2-, 3- or 4-position with regard to nitrogen of the pyridine ring in aldehyde component of the L-tryptophan derivative Schiff bases and corresponding copper complexes essentially change the biological activity of the compounds. The carboxaldehyde group at 2- and 4-positions leads to the higher cytotoxic activity, than that of at 3-position, and the presence of the copper in the complexes increases the cytotoxicity. Based on toxicity classification data, the compounds with non-toxic profile were identified, which can be used as new entities in the drug development process using Schiff base scaffold.

The 18th FRAME Annual Lecture, October 2019: Human In Silico Trials in Pharmacology

2019 ◽  
Vol 47 (5-6) ◽  
pp. 221-227
Author(s):  
Blanca Rodriguez
Keyword(s):  
Drug Development ◽  
In Silico ◽  
Drug Testing ◽  
Development Process ◽  
Computer Modelling ◽  
Current Knowledge ◽  
Magnetic Resonance Images ◽  
Population Heterogeneity ◽  
Drug Development Process

Safety and efficacy testing is a crucial part of the drug development process, and several different methods are used to obtain the necessary data (e.g. in vitro testing, animal trials and clinical trials). Our group has been investigating the potential of modelling and simulation as an alternative approach to some of the methods used for testing drugs for cardiac effects. To achieve our goal of developing and promoting novel approaches in drug development, we formed multidisciplinary collaborations that included clinicians, computer scientists and biologists. Our in silico models are based on human data (e.g. magnetic resonance images, electrocardiogram) and on current knowledge of human electrophysiology, thus generating predictions that are directly applicable to humans. Such models are a particularly powerful tool because they encompass different sources of population heterogeneity, which is crucial for drug testing and for assessing how interindividual variability might affect clinical endpoints. Our group has shown that computer modelling can be used to predict the effects of a test drug in a virtual population or in combination with machine learning to predict different phenotypes when a drug is given to a diseased population. Furthermore, our user-friendly drug testing software is freely available and is being adopted by industry in their drug development process. We have been engaging with industry and regulators to show that our models can contribute to the replacement of animals in drug development. Our ambition is to generate models for simulation of different diseases and therapies for investigations from subcellular to whole organ.

scholarly journals Homobivalent Lamellarin-Like Schiff Bases: In Vitro Evaluation of Their Cancer Cell Cytotoxicity and Multitargeting Anti-Alzheimer’s Disease Potential

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 359
Author(s):  
Alisa A. Nevskaya ◽  
Lada V. Anikina ◽  
Rosa Purgatorio ◽  
Marco Catto ◽  
Orazio Nicolotti ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Schiff Base ◽  
Schiff Bases ◽  
Search Algorithm ◽  
Biological Activities ◽  
Target Prediction ◽  
Drug Target Prediction ◽  
Micromolar Range

Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-a]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 μM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer’s disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent para-phenylene DHPPIQ Schiff base 14 exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with Ki in the low micromolar range (4.69 μM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC50) = 12 μM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced β-amyloid (Aβ)1–40 aggregation (IC50 = 13 μM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base 9.

scholarly journals Challenges and Tools for In Vitro Leishmania Exploratory Screening in the Drug Development Process: An Updated Review

Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1608
Author(s):  
Anita Cohen ◽  
Nadine Azas
Keyword(s):  
Side Effects ◽  
Drug Development ◽  
Development Process ◽  
Screening Tools ◽  
Sand Fly ◽  
Drug Development Process ◽  
Major Health Problem ◽  
Vector Borne Diseases ◽  
Antileishmanial Drug

Leishmaniases are a group of vector-borne diseases caused by infection with the protozoan parasites Leishmania spp. Some of them, such as Mediterranean visceral leishmaniasis, are zoonotic diseases transmitted from vertebrate to vertebrate by a hematophagous insect, the sand fly. As there is an endemic in more than 90 countries worldwide, this complex and major health problem has different clinical forms depending on the parasite species involved, with the visceral form being the most worrying since it is fatal when left untreated. Nevertheless, currently available antileishmanial therapies are significantly limited (low efficacy, toxicity, adverse side effects, drug-resistance, length of treatment, and cost), so there is an urgent need to discover new compounds with antileishmanial activity, which are ideally inexpensive and orally administrable with few side effects and a novel mechanism of action. Therefore, various powerful approaches were recently applied in many interesting antileishmanial drug development programs. The objective of this review is to focus on the very first step in developing a potential drug and to identify the exploratory methods currently used to screen in vitro hit compounds and the challenges involved, particularly in terms of harmonizing the results of work carried out by different research teams. This review also aims to identify innovative screening tools and methods for more extensive use in the drug development process.

scholarly journals Copper(II) complexes of Schiff base ligands as promising anticancer agents

2016 ◽  
Author(s):  
Elżbieta Hejchman ◽  
Barbara Sowirka ◽  
Magdalena Tomczyk ◽  
Dorota Maciejewska
Keyword(s):  
Schiff Base ◽  
Anticancer Activity ◽  
Schiff Bases ◽  
Anticancer Agents ◽  
Copper Complexes ◽  
World Health ◽  
Anticancer Activities ◽  
Schiff Base Ligands ◽  
Drug Induced

Based on World Health Organization (WHO) report, it was estimated that one in five people before age 75 will suffer from cancer during their lifetime, and more than 13 million cancers death will happen in 2030. Chemotherapy is a basic approach for the treatment of cancer diseases. However, because of drug resistance and considerable side effects drug-induced toxicity, the discovery of new metal analogs with promising activity and high therapeutic index is an urgent need. The fundamental role of copper and the recognition of its complexes as important bioactive compounds in vitro and in vivo aroused an ever-increasing interest in these agents as potential drugs for therapeutic intervention in various diseases. Schiff bases are a critical class of compounds in medical chemistry that have demonstrated significant chemotherapeutic and antibacterial application. Schiff base Cu(II) complexes revealed great potential for antiproliferative, antibacterial, and gastroprotective activity. Coumarins are a wide class of natural and synthetic compounds that showed diverse pharmacological activities including anticancer activity. Among the wide variety of coumarins, 7-hydroxycoumarin derivatives have been shown to possess desirable antiproliferative activities. In particular, their antibacterial, antifungal and anticancer activities make the compounds attractive for further derivatization and screening as novel therapeutic agents. Taking these compounds as lead, we have designed and synthesized a series of new copper(II) complexes with coumarin-derived Schiff base ligands. Two series of Schiff bases were prepared by condensation of 8-formyl-7-hydroxy-4-methylcoumarin and 8-acetyl-7-hydroxy-4-methylcoumarin with p-substituted aniline derivatives. These compounds were used as ligands in the synthesis of copper(II) complexes. The obtained Schiff bases as well as copper complexes are mostly novel molecules. Only the products of condensation 8-formyl-7-hydroxy-4-methylcoumarin with p-toluidine and 8-acetyl-7-hydroxy-4-methylcoumarin with p-toluidine and its copper(II) complex were synthesized, but the anticancer activity of these compounds was not determined. The assay of their cytotoxic activity is in progress. Preliminary, we have identified two copper(II) coordination compounds of 7-hydroxy-8-[1-(4-methoxyphenyl imino)ethyl]-4-methyl-2H-chromen-2-one and 7-hydroxy-8-[1-(4-hydroxyphenyloimino)ethyl]-4-methyl-2H- chromen-2-one having dose-dependent antiproliferative activity on HeLa cancer cell line. Additionally, the Schiff bases – derivatives of substituted salicylaldehydes and 2-hydroxyacetophenones condensed with appropriate anilines were prepared. Such compounds have been reported in scientific papers, their copper complexes have not been assayed yet, and may serve as an useful tool in QSAR investigation.

scholarly journals Copper(II) complexes of Schiff base ligands as promising anticancer agents

2016 ◽  
Author(s):  
Elżbieta Hejchman ◽  
Barbara Sowirka ◽  
Magdalena Tomczyk ◽  
Dorota Maciejewska
Keyword(s):  
Schiff Base ◽  
Anticancer Activity ◽  
Schiff Bases ◽  
Anticancer Agents ◽  
Copper Complexes ◽  
World Health ◽  
Anticancer Activities ◽  
Schiff Base Ligands ◽  
Drug Induced

Based on World Health Organization (WHO) report, it was estimated that one in five people before age 75 will suffer from cancer during their lifetime, and more than 13 million cancers death will happen in 2030. Chemotherapy is a basic approach for the treatment of cancer diseases. However, because of drug resistance and considerable side effects drug-induced toxicity, the discovery of new metal analogs with promising activity and high therapeutic index is an urgent need. The fundamental role of copper and the recognition of its complexes as important bioactive compounds in vitro and in vivo aroused an ever-increasing interest in these agents as potential drugs for therapeutic intervention in various diseases. Schiff bases are a critical class of compounds in medical chemistry that have demonstrated significant chemotherapeutic and antibacterial application. Schiff base Cu(II) complexes revealed great potential for antiproliferative, antibacterial, and gastroprotective activity. Coumarins are a wide class of natural and synthetic compounds that showed diverse pharmacological activities including anticancer activity. Among the wide variety of coumarins, 7-hydroxycoumarin derivatives have been shown to possess desirable antiproliferative activities. In particular, their antibacterial, antifungal and anticancer activities make the compounds attractive for further derivatization and screening as novel therapeutic agents. Taking these compounds as lead, we have designed and synthesized a series of new copper(II) complexes with coumarin-derived Schiff base ligands. Two series of Schiff bases were prepared by condensation of 8-formyl-7-hydroxy-4-methylcoumarin and 8-acetyl-7-hydroxy-4-methylcoumarin with p-substituted aniline derivatives. These compounds were used as ligands in the synthesis of copper(II) complexes. The obtained Schiff bases as well as copper complexes are mostly novel molecules. Only the products of condensation 8-formyl-7-hydroxy-4-methylcoumarin with p-toluidine and 8-acetyl-7-hydroxy-4-methylcoumarin with p-toluidine and its copper(II) complex were synthesized, but the anticancer activity of these compounds was not determined. The assay of their cytotoxic activity is in progress. Preliminary, we have identified two copper(II) coordination compounds of 7-hydroxy-8-[1-(4-methoxyphenyl imino)ethyl]-4-methyl-2H-chromen-2-one and 7-hydroxy-8-[1-(4-hydroxyphenyloimino)ethyl]-4-methyl-2H- chromen-2-one having dose-dependent antiproliferative activity on HeLa cancer cell line. Additionally, the Schiff bases – derivatives of substituted salicylaldehydes and 2-hydroxyacetophenones condensed with appropriate anilines were prepared. Such compounds have been reported in scientific papers, their copper complexes have not been assayed yet, and may serve as an useful tool in QSAR investigation.

scholarly journals Characterization of Antimicrobial, Antioxidant, and Leishmanicidal Activities of Schiff Base Derivatives of 4-Aminoantipyrine

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2696 ◽  
Author(s):  
Teran ◽  
Guevara ◽  
Mora ◽  
Dobronski ◽  
Barreiro-Costa ◽  
...  
Keyword(s):  
Schiff Base ◽  
Schiff Bases ◽  
Antimicrobial Activities ◽  
Drug Candidates ◽  
Development Of Resistance ◽  
Schiff Base Derivatives ◽  
Wide Range ◽  
Derivatives Of

Our main interest is the characterization of compounds to support the development of alternatives to currently marketed drugs that are losing effectiveness due to the development of resistance. Schiff bases are promising biologically interesting compounds having a wide range of pharmaceutical properties, including anti-inflammatory, antipyretic, and antimicrobial activities, among others. In this work, we have synthesized 12 Schiff base derivatives of 4-aminoantipyrine. In vitro antimicrobial, antioxidant, and cytotoxicity properties are analyzed, as well as in silico predictive adsorption, distribution, metabolism, and excretion (ADME) and bioactivity scores. Results identify two potential Schiff bases: one effective against E. faecalis and the other with antioxidant activity. Both have reasonable ADME scores and provides a scaffold for developing more effective compounds in the future. Initial studies are usually limited to laboratory in vitro approaches, and following these initial studies, much research is needed before a drug can reach the clinic. Nevertheless, these laboratory approaches are mandatory and constitute a first filter to discriminate among potential drug candidates and chemical compounds that should be discarded.

Intelligent Drug Development

2014 ◽  
Author(s):  
Michael Tansey
Keyword(s):  
Clinical Trials ◽  
Cost Effectiveness ◽  
Drug Development ◽  
Clinical Research ◽  
Development Process ◽  
Drug Development Process ◽  
Individual Trial ◽  
Specific Technology

Clinical research is heavily regulated and involves coordination of numerous pharmaceutical-related disciplines. Each individual trial involves contractual, regulatory, and ethics approval at each site and in each country. Clinical trials have become so complex and government requirements so stringent that researchers often approach trials too cautiously, convinced that the process is bound to be insurmountably complicated and riddled with roadblocks. A step back is needed, an objective examination of the drug development process as a whole, and recommendations made for streamlining the process at all stages. With Intelligent Drug Development, Michael Tansey systematically addresses the key elements that affect the quality, timeliness, and cost-effectiveness of the drug-development process, and identifies steps that can be adjusted and made more efficient. Tansey uses his own experiences conducting clinical trials to create a guide that provides flexible, adaptable ways of implementing the necessary processes of development. Moreover, the processes described in the book are not dependent either on a particular company structure or on any specific technology; thus, Tansey's approach can be implemented at any company, regardless of size. The book includes specific examples that illustrate some of the ways in which the principles can be applied, as well as suggestions for providing a better context in which the changes can be implemented. The protocols for drug development and clinical research have grown increasingly complex in recent years, making Intelligent Drug Development a needed examination of the pharmaceutical process.

Microphysiological systems: What it takes for community adoption

2021 ◽  
pp. 153537022110088
Author(s):  
Passley Hargrove-Grimes ◽  
Lucie A Low ◽  
Danilo A Tagle
Keyword(s):  
Rare Diseases ◽  
Development Process ◽  
Emerging Technology ◽  
National Institutes Of Health ◽  
Drug Development Process ◽  
Microphysiological Systems ◽  
Pediatric Populations ◽  
Neural Disorders ◽  
Future Path

Microphysiological systems (MPS) are promising in vitro tools which could substantially improve the drug development process, particularly for underserved patient populations such as those with rare diseases, neural disorders, and diseases impacting pediatric populations. Currently, one of the major goals of the National Institutes of Health MPS program, led by the National Center for Advancing Translational Sciences (NCATS), is to demonstrate the utility of this emerging technology and help support the path to community adoption. However, community adoption of MPS technology has been hindered by a variety of factors including biological and technological challenges in device creation, issues with validation and standardization of MPS technology, and potential complications related to commercialization. In this brief Minireview, we offer an NCATS perspective on what current barriers exist to MPS adoption and provide an outlook on the future path to adoption of these in vitro tools.

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